JPH0625250A - Thieno(3,4-d)imidazole derivative, its production and pharmaceutical agent for circulatory organ containing the derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having excellent hypotensive action and useful as a treating agent for circulatory diseases. CONSTITUTION:The compound of formula I [R<1> and R<2> are H, OH, halogen, alkyl, lower alkoxy, etc.; R<3> is alkyl, lower alkylthio, etc.; R<4> is H, nitro, cyano, etc.; R<5> is H, halogen or lower alkoxy; A is group of formula II, formula III, etc. (X is single bond or bond interposed with spacer; Y is methylene, C, N, etc.)], e.g. 2-butyl-4-methyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[ 3,4- d]imidazole. The compound of formula I can be produced by reacting a compound of formula IV with a compound of formula V (W is halogen, alkylsulfonyloxy or arylsulfonyloxy) in the presence of a base (e.g. sodium hydride) in a solvent (e.g. THF) at -20 to +100 deg.C. The compound is useful for the treatment of hypertension, cardiopathy, cerebral apoplexy, renal diseases developing proteinuria, arteriosclerosis, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has an antagonistic action against angiotensin II known as an endogenous vasoconstrictor, and is associated with hypertension, heart disease, stroke, renal disease with white urine, arteriosclerosis, etc. , A novel thieno [3,4-d] imidazole derivative effective as a remedy for cardiovascular diseases and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art The renin-angiotensin system (RAS), which plays an important role in regulating blood pressure in the living body, is composed of renin whose main production unit is the kidney, renin substrate (angiotensinogen) produced mainly in the liver, and renin. Angiotensin I (A resulting from the reaction of the renin substrate
I), angiotensin II (AII) and angiotensin III (AIII) produced by the action of angiotensin converting enzyme (ACE). The center of activity of this system is AII, which has an action of increasing blood pressure through peripheral / central actions in the living body, and is considered to be involved in cardiovascular disorders such as hypertension.

Therefore, by suppressing the action of AII, the pathological condition of AII-induced hypertension can be relieved.
As an antagonist that suppresses the binding of AII to the AII receptor, various synthetic studies of AII-like peptides have been conducted so far. As a result, [Sar ¹ , Ala ⁸ ] AII was found.
(Salalacin) can be mentioned as one of the potent AII antagonists. However, palatable AII antagonists such as salaracin show AII antagonism and
Since it has an agonistic property to the receptor, it may exert a pressor effect under some conditions, and it is unstable because it is a peptide derivative, so it is rapidly degraded in the body and shows an effect when administered orally. It has some drawbacks such as not being present.

On the other hand, recently, a non-peptide imidazole derivative having a hypotensive action based on AII antagonism even after oral administration has been found and disclosed (JP-A-56-71073 and JP-A-63). No. 23868). After that, in JP-A-1-287071, pyrrole, pyrazole and triazole derivatives are further disclosed in JP-A-3-5480, 3-95181 and 3-1.
06879, 3-1888076, 3-236377.
Imidazopyridine derivatives are disclosed as non-peptidic AII antagonists in Japanese Patent Laid-Open Publication No. 0-456510 and the like. Further, JP-A-4-9373 discloses a benzimidazole derivative, and JP-A-3-148279 discloses a thienoimidazole derivative, an imidazoimidazole derivative and an imidazopyrazole derivative which are described as having an AII receptor antagonistic action. It is illustrated.

[0005]

Problems to be Solved by the Invention Saralasin, which is a peptide type AII antagonist, is one of the most potent antagonists to AII. However, due to its agonistic properties, salalacin, on the contrary, elicits a pressor effect when elevated blood pressure is not maintained by AII. Further, since it is a peptide derivative, it is unstable and easily decomposed in vivo, and its pharmacological action is short. Therefore, no effect was observed with oral administration,
The effect is exhibited only by parenteral administration, and it is used only as a diagnostic agent for renin-dependent hyperemia.

On the other hand, the known non-peptide AII antagonist is A
Since it has no agonistic properties for the II receptor, it does not exhibit a pressor action and can be administered orally, but it is hard to say that the hypotensive action during oral administration is sufficient when considering its application as a drug. In order for an AII antagonist to be a clinically useful drug for treating cardiovascular diseases such as hypertension, heart disease, and stroke, it has a high antagonistic effect on the AII receptor, and also in oral administration. It is desirable to have a long-lasting and strong blood pressure lowering effect, and these points can be satisfied.
II antagonists are desired.

[0007]

[Means for Solving Problems] Japanese Patent Laid-Open No. 14827/1993
No. 9 discloses an unsubstituted thienoimidazole derivative which is described as having an AII antagonistic action.
There is no description of specific activity regarding AII antagonism and hypotensive action. Therefore, the present inventors have selected a specific compound among these derivatives, that is, an unsubstituted thieno [3,4-d] imidazole derivative [A], which is the only example in this patent, as an AII antagonistic action and a hypotensive effect. When tested for action, although an AII antagonism was observed, the hypotensive action by intravenous and oral administration was weak,
It was not sufficiently satisfactory for practical use as a medicine.

[0008]

[Chemical 21] On the other hand, the 4- or 6- and 6-position-substituted thieno [3,4-d] imidazole derivative of the present invention has a strong action, and provides a practicable drug which cannot be predicted from the result of the unsubstituted form. It is a thing.

The present invention has the general formula

[Chemical formula 22] [Wherein R ¹ and R ² are hydrogen atom, hydroxyl group, halogen atom, alkyl group, hydroxyalkyl group, lower alkoxy group, formyl group, cyano group, carbamoyl group, lower alkoxycarbonyl group, carboxy group,

[Chemical formula 23] (In the formula, R ⁶ may be a hydrogen atom, an alkyl group, R ⁷ and R ⁸ may be the same or different, and a hydrogen atom, a lower alkoxycarbonyl group, a carboxy group, an optionally protected tetrazole group or an aralkyl group, R ⁹ , R ¹⁰ may be the same or different, a hydrogen atom, an alkyl group, an optionally substituted aryl group or an aralkyl group, V is an oxygen atom, a nitrogen atom, a carbon atom, a sulfur atom, ═CH—R ¹¹ or = N-R ^11, R ¹¹ is alkyl, substituted optionally may be an aryl group, an aralkyl group or an aroyl group, m is an integer from 1 to 6, q is an integer of 1 to 3), an aryl group or an aralkyl Base,

R ³ is an alkyl group, a cyclo-lower alkyl group or a lower alkylthio group, R ⁴ is a hydrogen atom, a nitro group, a cyano group, an optionally substituted amino group, a lower alkoxycarbonyl group, a carboxy group or a protected group. Optionally a tetrazole group, R ⁵ is a hydrogen atom, a halogen atom or a lower alkoxy group, A is

[Chemical formula 24] (In the formula, X represents a single bond or a bond through a spacer having two or less atomic chains, Y represents a methylene carbon,
A nitrogen atom, an oxygen atom or a sulfur atom which may be substituted) is represented by the formula [1], or a salt thereof.

Thieno [3,4-, represented by the general formula [I]
d] Examples of the halogen atom for R ¹ , R ² and R ⁵ of the imidazole derivative include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. R ¹ , R ² , R ³ ,
Examples of the alkyl group for R ⁶ , R ⁹ , R ¹⁰ and R ¹¹ include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, isoamyl, hexyl, C1-C1 such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl
Examples thereof include two linear or branched alkyl groups and an alkyl group substituted with a halogen atom such as trifluoromethyl and pentafluoropropyl. The hydroxyalkyl group for R ¹ and R ² is a hydroxyalkyl group having 1 to 4 carbon atoms such as hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl, which may be substituted. , Its substituents are methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, methoxymethyl, methoxyethyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxy. Ethyl, propoxypropyl, propoxybutyl, isopropoxymethyl,
Examples include isopropoxyethyl, isopropoxypropyl, isopropoxybutyl and the like.

Lower alkoxy groups for R ¹ , R ² and R ⁵ include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy,
1 to 6 carbon atoms such as tertiary butoxy and n-pentyloxy
A straight-chain or branched lower alkoxy group. The carbamoyl group for R ¹ and R ² may be substituted, and the substituent may be a lower alkyl group having 1 to 5 carbon atoms, which may be linear or branched, and examples thereof include methyl and ethyl. , Propyl, isopropyl, butyl, secondary butoxy, tertiary butoxy, pentyl, secondary pentyl and the like.

The aryl group and aralkyl group for R ¹ , R ² , R ⁹ , R ¹⁰ and R ¹¹ include, for example, substituted or unsubstituted aryl groups such as benzene ring, pyridine ring and imidazole ring, benzyl and pyridylmethyl. A substituted or unsubstituted aralkyl group such as pyridylethyl, imidazolemethyl, furylmethyl, and thienylmethyl.The substituents include a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, and a mono-lower alkylamino group,
A di-lower alkylamino group and a sulfamoyl group, which may be the same or different at any position depending on their substituents.
~ 3 substituted.

Lower alkoxycarbonyl groups for R ¹ , R ² , R ⁴ , R ⁷ and R ⁸ include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, secondary butoxy. Examples thereof include linear or branched lower alkoxycarbonyl groups having 1 to 6 carbon atoms such as carbonyl, tertiary butoxycarbonyl, and n-pentylcarbonyl. Examples of the aralkyl group of R ⁷ and R ⁸ include substituted or unsubstituted aralkyl groups such as benzyl, pyridylmethyl, imidazolemethyl, furylmethyl, thienylmethyl, and the like.
1 to 3 substituents which are the same or different at arbitrary positions are substituted with a hydroxyl group, a lower alkyl group, a lower alkoxy group, a mono-lower alkylamino group, a di-lower alkylamino group and a sulfamoyl group.

Cyclo lower alkyl groups for R ³ include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cyclobutenyl, cyclopentenyl, cyclo Hexenyl, cyclobutenylmethyl,
Cyclopentenylmethyl, cyclohexenylmethyl, cyclobutenylethyl, cyclopentenylethyl, cyclohexenylethyl, cyclohexenylbutyl and the like may form a ring having 3 to 6 carbon atoms and may have an unsaturated bond in the ring. , A cyclo lower alkyl group in which the ring formed is directly bonded or is bonded at a carbon number of 1 to 4 carbon atoms. Examples of the lower alkylthio group for R ³ include methylthio, ethylthio, 1-methylethylthio, propylthio, 1-methylpropylthio, 1-
Ethylpropylthio, n-butylthio, 1-methyl-n
Examples thereof include linear or branched lower alkylthio groups having 1 to 6 carbon atoms such as -butylthio, 1-ethyl-n-butylthio, n-pentylthio and n-hexylthio.

The tetrazole group for R ⁴ , R ⁷ and R ⁸ may be protected by an easily removable protecting group such as a trityl group, a p-nitrobenzyl group and a 1-ethoxyethyl group. The amino group for R ⁴ may be substituted, and examples of the substituent include a lower alkyl group, an aralkyl group, an acyl group, a trifluoromethanesulfonyl group and the like, and examples of the substituent include methyl, ethyl, butyl, hexyl and the like. A lower alkyl group having 1 to 6 carbon atoms,
Substituted or unsubstituted aralkyl groups such as benzyl and pyridylmethyl, acyl groups having 1 to 6 carbon atoms such as acetyl, propionyl and butyryl, and aroyl groups such as benzoyl can be mentioned. , A halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a mono-lower alkylamino group, a di-lower alkylamino group, and a sulfamoyl group, which are substituted at the same positions or differently at 1 to 3 positions.

As a spacer having two or less atomic chains for X, --CH _2- , --O--, --S--, --NH--, --C is used.
H = CH -, - Z- CH (R 12) - , and the like.
Examples of the substituent R ¹² include a tetrazole group protected by an easily removable protecting group such as a lower alkoxycarbonyl group, a carboxy group, a tetrazole group, trityl, p-nitrobenzyl and 1-ethoxyethyl group.
Examples of Y and Z include a methylene carbon, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom, and examples of the substituent include a lower alkyl group, an acyl group such as acetyl and propionyl, and an aroyl group such as benzoyl. Be done.

(Production Method) The compound of the above general formula (I) can be produced, for example, by the following method. The substituent W in the formula III represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, and the substituent U in the formula VI represents an imino lower alkyl ether, imino lower alkyl thioether, carboxy group, amidine group, aldehyde group or cyano group. Indicates. Also R ¹ ~
R ⁵ , R ²¹ and A have the meanings given above.

Reaction (a)

[Chemical 25] Reaction (b)

[Chemical formula 26] Reaction (c)

[Chemical 27] Reaction (d)

[Chemical 28] Reaction (e)

[Chemical 29]

The reaction (a) is carried out by reacting the alkylating agent (III) in the presence of a base in an organic solvent to carry out alkylation. Using 1 to 3 mol of a base and 1 to 3 mol of an alkylating agent (III) to 1 mol of a compound (II), usually tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile. , A single solvent such as acetone or ethyl methyl ketone, or a mixed solvent appropriately combined. As the base, sodium hydroxide, potassium hydroxide, sodium methylate, sodium hydride,
Tertiary butoxy potassium, sodium carbonate, etc. are used. Examples of W of the alkylating agent (III) include a chlorine atom, a bromine atom, a halogen atom of an iodine atom, an alkylsulfonyloxy group such as a methanesulfonyloxy group, or an arylsulfonyloxy group such as a p-toluenesulfonyloxy group. To be The reaction conditions will differ depending on the combination of the base used and the alkylating agent (III), but the reaction temperature will be -20 ° C to the boiling temperature of the solvent, preferably-.
The temperature is in the range of 20 ° C to + 100 ° C, and the reaction is completed in 1 to 48 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

In the reaction (b), a cyano group substituted on the benzene ring of the compound (Ia) in an organic solvent is reacted with various azides to convert it into a tetrazole compound (Ib). Azide compounds 1 to 3 relative to 1 mol of compound (Ia)
It is used in a molar amount and is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, toluene or benzene. Examples of the azide compound include trialkyltin azide or triphenyltin azide and hydrazoic acid. When an organotin azide compound is used, it is reacted in benzene or toluene while heating under reflux for about 10 to 48 hours. When reacting hydrazoic acid, sodium azide and ammonium chloride are used in an amount about 3 times the molar amount of compound (Ia), preferably in the presence of a catalytic amount of lithium chloride, in dimethylformamide at a reaction temperature of 100 to 1
The reaction is completed at 1 to 7 days at 30 ° C. During this period, it is preferable to promote the reaction by adding an appropriate amount of sodium azide and ammonium chloride.

In the reaction (c), a substituent (R ²¹ ) is introduced at the 4-position of the thieno [3,4-d] imidazole ring in the presence of a base in an organic solvent to obtain the compound (Id).
It is generally carried out in a solvent such as tetrahydrofuran, ether, dioxane or the like using 1 to 3 mol of a base and about 2 to 6 mol of an alkylating agent or dimethylformamide with respect to compound (Ic). As the base, n-butyl lithium, tertiary butyl lithium, lithium diisopropylamide, etc. are used. Alkylating agents include substituted lower halogenated (C ₁ -C ₆ ) alkyl (eg chloride, bromide,
However, it may be used as a substituted sulfonic acid ester or the like. The reaction conditions vary depending on the combination of the base, alkylating agent and dimethylformamide used, but the reaction temperature is -100 ° C to + 50 ° C, preferably -78 ° C to room temperature, and the reaction is 1 to 20 ° C.
Complete in time. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

In the reaction (d), anilide obtained by reducing the nitro group is subjected to intramolecular dehydration ring closure to produce thieno [3,4-
d] to obtain an imidazole derivative (I). The reducing agent is used in an amount of about 2 to 10 mol per 1 mol of the compound (IV). Examples of the reducing agent include metals such as iron, zinc and tin, and the reducing agent can be usually used under acidic or alkaline conditions. Examples of the solvent include alcohol solvents such as methanol and ethanol, ether solvents such as ethyl ether, tetrahydrofuran and dioxane, water, acetic acid,
Hydrochloric acid is used as a single solvent or a mixed solvent appropriately combined. The reaction conditions will differ depending on the combination of reducing agent, solvent and acid (or alkali) conditions used, but the reaction temperature will be -20 ° C to the boiling temperature of the solvent, preferably -20.
C. to + 80.degree. C., and the reaction is completed in 0.5 to 24 hours.

This reaction is carried out under neutral or acidic conditions in order to carry out the dehydration ring closure reaction after the reduction reaction. As the acid used to accelerate the reaction, acetic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid or the like can be used. As the solvent to be used, alcohol solvents such as methanol, ethanol and propanol, cellosolve solvents such as methyl cellosolve and ethyl cellosolve, ether solvents such as ethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform and methylene chloride. It is used as a system solvent, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, a single solvent such as acetonitrile, dimethyl sulfide, dimethylformamide and dimethylacetamide, or a mixed solvent appropriately combined. The reaction conditions will differ depending on the neutral conditions or the combination of acid and solvent used, but the reaction temperature will range from 0 ° C to the boiling temperature of the solvent,
It is preferably in the range of 0 ° C to 100 ° C, and the reaction is 1-2.
It will be completed in 4 hours.

In the reaction (e), the diamine derivative (V) is reacted with various compounds (VI) in an organic solvent to carry out a condensation ring closure reaction to convert it into a thieno [3,4-d] imidazole derivative (I). It is a thing. Examples of U of the compound (VI) include imino lower alkyl ether group, imino lower alkyl thioether group, carboxy group, amidine group,
Examples thereof include an aldehyde group and a cyano group, and the lower alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms. It is also possible to use the reagent (VI) in excess of about 1 to 10 moles per 1 mole of the compound (V) and use the reagent (VI) as a solvent. As the solvent to be used, alcohol solvents such as methanol, ethanol and propanol, cellosolve solvents such as methyl cellosolve and ethyl cellosolve, ether solvents such as ethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform and methylene chloride. System solvents, aromatic hydrocarbon solvents such as benzene, toluene, xylene, acetonitrile, dimethyl sulfide,
It is used as a single solvent such as dimethylformamide or dimethylacetamide, or as a mixed solvent appropriately combined. In order to accelerate the reaction, an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, or triethylamine, morpholine, pyridine, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc. It can be performed by adding the base. The reaction conditions will differ depending on the combination of reagent (VI), acid, base and solvent used, but are usually from −20 ° C. to the boiling temperature of the solvent, preferably −
The temperature is in the range of 20 ° C to + 120 ° C, and the reaction is completed in 1 to 48 hours.

After completion of the reaction, the reaction products obtained in the above reactions (a) to (e) can be isolated and purified by a known method such as extraction, recrystallization and column chromatography. The target product can be obtained easily. In addition, these compounds (I) are salts with physiologically acceptable acids or bases by a conventional method, acetates with compounds,
It can be led to salts with organic acids such as oxalates, succinates, and maleates, salts with alkali metals such as sodium salts and potassium salts, and salts with alkaline earth metals such as calcium salts. Of these compounds, the starting compound (I
I), (III), (IV) and (V) can be synthesized by, for example, the method described in the following report or a method analogous thereto.

A. Hunger et al. Helv. Chim. Acta., 43, 1032
(1960). RC De Seims, J. Org. Chem., 27, 2163 (1962). AF Casy et al. J. Chem. Soc., (C), 1966, 1500. RE Lyle et al. J. Org. Chem., 40, 438 (1975). M. Itaya et al. Yakugaku Zasshi, 82, 1 (1965). Wilhelm et al. Justus Liebigs Ann. Chem., 536, 128 (19
38). H. Fiesselman Angew. Chem., 71, 377 (1959). AI Meyers et al. J. Org. Chem., 43, 1372 (1978). JP Hurwitz et al. Ibid., 26, 3392 (1961). DJ Carini J. Med. Chem., 34, 2525 (1991). S. Kozima et al. J. Organommetallic Chem., 1971, 337. In addition, the starting compounds (IV) and (V) are reacted (f),
It can be easily obtained by the method described in (g) or a method analogous thereto.

Reaction (f)

[Chemical 30] Reaction (g)

[Chemical 31]

In the reaction (f), the acyl compound (VIII) synthesized from the compound (VII) according to a known method is converted into a known nitration reagent (for example, fuming nitric acid-acetic anhydride, nitric acid-sulfuric acid, potassium nitrate-sulfuric acid). And the like) to give a nitro compound (IX), and carry out alkylation by the same method as in the reaction (a) or a method analogous thereto to obtain the starting compound (IV).
In reaction (g), compound (XI) obtained by alkylating carbamic acid ester (X) in the same manner as in reaction (f).
By reacting with a reducing agent (for example, stannic chloride, iron, zinc-hydrochloric acid, hydrazine-ferric chloride), a diamine body (V) as a raw material compound is obtained.

[0030]

ACTION AND EFFECT OF THE INVENTION The AII antagonistic action and hypotensive action of representative compounds of the compound [I] of the present invention are described in detail below. (Test compound and control drug) 2-butyl-4-methyl-
1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole (Compound 1), 2-butyl-4-formyl-1
-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole (Compound 2), 2-butyl-4-hydroxymethyl-1-[[ 2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl] thieno [3,4-d]
Imidazole (compound 3), 2-butyl-1-[[2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Il] methyl] thieno [3,4-d] imidazole-4
-Carboxylic acid (compound 4), (E) -3- [2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d ] Imidazol-4-yl] -2- (2-thienyl) -2-
Propenoic acid (Compound 5) 2-Ethyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-6-
Carboxylic acid (compound 6), 2-propyl-1-[[2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Il] methyl] thieno [3,4-d] imidazole-6
A carboxylic acid (compound 7),

Methyl 2-propyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (Compound 8) , 2-propyl-1-[[5'-
Chloro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid (Compound 9), 2-butyl-
1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid (Compound 10), 2-cyclopropyl-1- [[2 '-(1H-tetrazole-5-
Il) biphenyl-4-yl] methyl] thieno [3,4
-D] imidazol-6-carboxylic acid (Compound 11),
4-morpholinomethyl-2-propyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-6-
Carboxylic acid (Compound 12), 4- (4-phenylpiperazinylmethyl) -2-propyl-1-[[2 '-(1H
-Tetrazol-5-yl) biphenyl-4-yl] thieno [3,4-d] imidazol-6-carboxylic acid (compound 13), 6-methyl-2-propyl-1-[[2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Il] methyl] thieno [3,4-d] imidazole-4
-Carboxylic acid (Compound 14), 2-butyl-1-
[[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole (Control A).

The unsubstituted thieno [3,4-d] imidazole derivative (A) described in JP-A-3-148279 is the only example described as having an AII receptor antagonistic action. The control agent A was used for the purpose of comparison with the compound of the present invention because there is no description of specific activity regarding AII antagonism and hypotensive action. 1. [AII contraction antagonism] Male Hartley guinea pigs were slaughtered and exsanguinated, the abdomen was opened and the ileum was excised to prepare a longitudinal muscle sample of about 2 cm. Three
95% O ₂ + 5% CO _{2 in} Magnus tube kept at 7 ℃
The mixed gas of was aerated. Krebs-bicarbon
The ate solution was filled and the sample was suspended by applying a load of 0.5 g. After recording the contraction of control by cumulative administration of AII10 ^-10 ~10 ^-7 M of 30-minute intervals, the number dose of each test drug was administered AII administration 15 minutes prior to the low concentration, AII10 under test drug co ^{- The} contraction by administration of ¹⁰ to 10 ⁻⁶ M was recorded. Control contraction AII The contraction height of 10 ^-7 M contraction was defined as 100%, and AII in the presence of each concentration of the test drug.
The contraction rate of 10 ⁻⁷ M contraction was calculated, and the 50% inhibitory concentration (IC ₅₀ value, molar concentration) was determined from the calculated value. The results are shown in Table 1.

[0033]

[Table 1]

2. [Inhibitory effect on AII pressor response] Male SD rats were used. Under anesthesia with pentobarbital Na (60 mg / kg, intraperitoneal administration), the femoral artery and femoral vein were cannulated and left for 2 hours or more after the operation. Connect the arterial cannula to a blood pressure transducer to record the mean blood pressure in the awake state and use it as a control before administration of the study drug.
Pressurization by intravenous administration of (0.1 μg / kg) was recorded.
The test drug was intravenously administered, and then AII was intravenously administered in each measurement, and the pressor response was similarly recorded. The suppression rate was calculated by comparing the pressor response before and after administration of the test drug. The results are shown in Table 2.

[0035]

[Table 2] * 1): NT = not tested * 2): ++ 70% ≧ ++ ≧ 50%> + ≧ 30%>
15%

From the results of the above-mentioned pharmacological experiment example, in comparison with the unsubstituted thieno [3,4-d] imidazole derivative (control drug A), 4- or 6-position substituted thieno [3, which is the compound of the present invention, is compared. It is clear that the 4-d] imidazole derivative has a remarkably excellent AII antagonistic action and hypotensive action. Further, the above compound (6) was replaced with 0.02N Na
Dilute with OH solution and add to a 6-week-old male ICR mouse 48m
After a single intravenous administration of a dose up to g / kg and observation for 7 days after the administration, no deaths were observed in any of the administration groups, and no particular problematic toxicity change was observed. Therefore, the compound (I) of the present invention strongly suppresses the vasoconstriction and blood pressure increasing actions by AII, exhibits a hypotensive action particularly in mammals, and is useful as a therapeutic agent for hypertension, It is useful as a therapeutic agent for cardiovascular diseases such as illness, stroke, renal disease with white urine, and arteriosclerosis. Moreover, the compound (I) of the present invention is highly safe and the value of the present invention is high as described above. ．
When used as a medicine, the compound (I) of the present invention is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, diluent, and powder, granules, tablets, capsules,
It can be administered orally or parenterally in a dosage form such as an injection. The dose varies depending on the target disease, symptom, administration subject, administration method, etc., but when administered as an adult essential hypertension therapeutic agent, the daily dose is 0.1 to 1 in oral administration.
It is preferable to administer a daily dose of 0.1 mg to 10 mg by intravenous injection in a divided dose of 2 to 3 times.

[0037]

EXAMPLES The production of the starting compound used in the present invention and the compound [I] of the present invention will be specifically and specifically described below, but the present invention is not limited thereto.

Reference Example 1 2-Methylthio-1H-thieno [3,4-d] imidazole 2-mercapto-1H-thieno [3,4-d] imidazole (165 mg) was dissolved by adding 6 ml of ethanol and 3 ml of water, followed by hydroxylation. Add 50 mg of sodium and 0.1 ml of methyl iodide and stir for 3 hours. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate.
Ethyl acetate was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and a melting point of 148-
2-methylthio-1H-thieno [3,4-d] imidazole (103 mg, yield 58.
8%). IRν _max (KBr): 3116, 3092, 302
0,2920,1476,1402,1376,131
2,1222,1176,1164,986 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 2.63
(3H, s), 6.60 (2H, bs).

The following compounds are obtained in the same manner as in Reference Example 1. Reference Example 2 2-Ethylthio-1H-thieno [3,4-d] imidazole Properties: Light brown needle crystals, melting point: 157-159 ° C, yield:
60.1% IRν _max (KBr): 3112, 3080, 298
4,2968,2896,2868,1474,145
0, 1404, 1376, 1266, 1222, 117
2,1162,980,814,744 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.42
(3H, t, J = 6.0 Hz), 3.26 (2H, q,
J = 6.0 Hz), 6.60 (2H, bs).

Reference Example 3 2-Propylthio-1H-thieno [3,4-d] imidazole Properties: brown powder, melting point: 108-112 ° C., yield: 7
8.9% IRν _max (KBr): 3112, 2964, 292
8,2868,2800,1462,1400,135
8,1174,744 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.03
(3H, t, J = 6.0 Hz), 1.75 (2H, qu
in, J = 6.0 Hz), 3.24 (2H, t, J =
6.0 Hz), 6.60 (2H, s).

Reference Example 4 2-Butylthio-1H-thieno [3,4-d] imidazole Properties: Light brown powder, melting point: 121-123 ° C., yield: 6
5.8% IRν _max (KBr): 3120, 3036, 295
2,2928, 1488, 1462, 1434, 140
0,1362,1304,1230,1210,117
0,968,718 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.86
(3H, t, J = 6.0 Hz), 1.06-1.86
(4 Hz, m), 3.20 (2H, t, J = 6.0H
z), 6.50 (2H, bs).

Reference Example 5 Methyl 3-butyrylaminothiophene-2-carboxylate 3-butyrylaminothiophene-2 under argon atmosphere
-Methyl carboxylate 7.85 g anhydrous methylene chloride 60
It is dissolved in ml, 10.4 ml of triethylamine is added under ice cooling and stirred for 10 minutes, then 7.8 ml of butyryl chloride is added dropwise and stirred for 30 minutes at the same temperature. Water is added to the reaction mixture and the mixture is extracted with methylene chloride. The methylene chloride layer is washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. Methylene chloride was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ether-hexane to give methyl 3-butyrylaminothiophene-2-carboxylate (10.6 g yield) as pale yellow needle crystals with a melting point of 70-71 ° C. Rate 93.7%). IRν _max (KBr): 3316, 2968, 169
6,1668,1578,1452,1424,139
8,1282,1244,1180,1102,108
2,778 cm ^-1 . NMR (CDCl ₃ ) δ: 1.02 (3H, t, J =
6.5 Hz), 1.52-2.00 (2H, m), 2.
43 (2H, t, J = 6.0 Hz), 3.89 (3H,
s). 7.45 (1H, d, J = 5.0Hz), 8.1
3 (1H, d, J = 5.0Hz), 9.74 (1H, b
s).

The following compound is obtained in the same manner as in Reference Example 5. Reference Example 6 Methyl 3-propionylaminothiophene-2-carboxylate Property: colorless powder, melting point: 74-75 ° C, yield: 85.6
% IRν _max (KBr): 3328, 1702, 166
4,1570,1440,1410,1376,135
2,1278, 1238, 1172, 1098, 106
8,942,914,842,792,780,68
4,654 cm ^-1 . NMR (CDCl ₃ ) δ: 1.25
(3H, t, J = 6Hz), 2.55 (2H, q, J =
7Hz), 3.89 (3H, s), 7.43 (1H,
d, J = 6 Hz), 8.13 (1H, d, J = 6H)
z).

Reference Example 7 Methyl 3-valerylaminothiophene-2-carboxylate Property: Yellow oily substance, yield: 92.9% IRν _max (neat): 3336, 3136, 310
0,2956,2872,1704,1680,141
6,1278,1102,1042,952,876,
840,780,682,650 cm ^-1 . NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 6
Hz), 1.10-1.90 (4H, m), 2.43
(2H, t, J = 6Hz), 3.86 (s, 3H),
7.43 (d, 1H, J = 6Hz), 8.13 (d, 1)
H, J = 6 Hz).

Reference Example 8 3-Cyclopropanecarbonylaminothiophene-2-
Methyl carboxylate Properties: colorless powder, melting point: 121-123 ° C, yield: 9
9.0% IRν _max (KBr): 3308, 3108, 168
0,1638,1578,1486,1450,141
0, 1386, 1276, 1174, 1090, 102
6,956,926,884,840,820,688
cm ^-1 . NMR (CDCl ₃ ) δ: 0.70 to 1.23 (4H,
m), 1.40-1.79 (1H, m), 3.89 (3
H, s), 7.43 (1H, d, J = 6 Hz), 8.0
9 (1H, d, J = 6 Hz).

Reference Example 9 Methyl 3-butyrylamino-5-methylthiophene-2-carboxylate Property: colorless oil, yield: 96.1% IRν _max (neat): 3332, 3120, 296
0,2872,1704,1680,1580,150
4,1454,1416,1276,1220,109
6,842 cm ^-1 . NMR (CDCl ₃ ) δ: 1.00 (3H, t, J =
6.5 Hz), 1.53-1.96 (2H, m), 2.
40 (2H, t, J = 6.5Hz), 2.46 (3H,
s), 3.83 (3H, s), 7.85 (1H, s),
9.35 (1H, bs).

Reference Example 10 Methyl 3-butyrylamino-4-nitrothiophene-2-carboxylate 2 ml of sulfuric acid was dissolved in 454 mg of methyl 3-butyrylaminothiophene-2-carboxylate, and 222 mg of potassium nitrate was added little by little under ice cooling. Stir for 20 minutes. The reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and the melting point was 141-from the elution part of ethyl acetate-hexane (1: 4).
3-Butyrylamino-4-as yellow needles at 143 ° C
Methyl nitrothiophene-2-carboxylate (160m
g, yield 29.5%). IRν _max (KBr): 3300, 3112, 296
0,1716,1672,1570,1518,149
6,1440,1428,1414,1358,128
2,1208,1114,904,762 cm ^-1 . NMR (CDCl ₃ ) δ: 1.02 (3H, t, J =
6.5 Hz), 1.53-1.96 (2H, m), 2.
44 (2H, t, J = 6.5Hz), 3.91 (3H,
s). 8.25 (1H, s), 9.14 (1H, s).

The following compound is obtained in the same manner as in Reference Example 10. Reference Example 11 4-Nitro-3-propionylaminothiophene-2-
Methyl carboxylate Properties: yellow powder, melting point: 146-148 ° C, yield: 3
8.4% IRν _max (KBr): 3334, 1716, 169
5,1578,1521,1479,1452,141
9, 1380, 1332, 1260, 1202, 116
1,1095,1074,1044,990,937,
813, 765 cm ^-1 . NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 6
Hz), 2.45 (2H, q, J = 6Hz), 3.89
(3H, s), 8.20 (1H, s).

Reference Example 12 Methyl 4-nitro-3-valerylaminothiophene-2-carboxylate Property: colorless powder, melting point: 123-124 ° C., yield: 1
9.3% IRν _max (KBr): 3308, 1714, 167
4,1568,1518,1496,1466,135
8,1282,1206,1000,956,898,
816,782,762 cm ^-1 . NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 6
Hz), 1.13-1.90 (4H, m), 2.43
(2H, t, J = 6Hz), 3.90 (3H, s),
8.20 (1H, s).

Reference Example 13 Methyl 3-cyclopropanecarbonylamino-4-nitrothiophene-2-carboxylate Property: yellow powder, melting point: 193-196 ° C., yield: 2
3.5% IRν _max (KBr): 3308, 3120, 171
4,1670, 1574, 1542, 1502, 144
0, 1418, 1392, 1358, 1276, 121
2,1194,1108,952,884,816,7
68 cm ^-1 . NMR (CDCl ₃ ) δ: 0.70-1.26 (4H,
m), 1.43-1.83 (1H, m), 3.90 (3
H, s), 8.20 (1H, s).

Reference Example 14 Methyl 3-butyrylamino-5-methyl-4-nitrothiophene-2-carboxylate Property: Light yellow powder, melting point: 133-134 ° C., yield: 5
9.8% IRν _max (KBr): 3356, 2960, 168
8, 1576, 1532, 1490, 1448, 140
6,1358,1274,1200,1112,768
cm ^-1 . NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.
52-1.96 (2H, m), 2.42 (2H, t, J
= 6 Hz), 2.65 (3H, s), 9.30 (1H,
bs).

Reference Example 15 3- [N-butyryl-N- [2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl]
Methyl amino-4-nitrothiophene-2-carboxylate Under argon atmosphere, 22 mg of 60% sodium hydride was suspended in 2 ml of anhydrous DMF, and methyl 3-butyrylamino-4-nitrothiophene-2-carboxylate 13 was cooled under ice-cooling.
A solution of 2 ml of anhydrous DMF containing 6 mg was added dropwise, and after stirring at the same temperature for 20 minutes, N-trityl-5- [4 '-(bromomethyl) biphenyl-2-yl] tetrazole 306
A solution of 3 mg of anhydrous DMF containing mg was added at the same temperature 1
Stir for 3 hours. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and 3- [N-butyryl-N- [2 '-(1-Trityltetrazol-5-yl) biphenyl-4-yl] methyl]
Methyl amino-4-nitrothiophene-2-carboxylate (182 mg, yield 59.8%) is obtained. IR ν _max (neat): 3064, 2964, 287
2,1730,1672,1552,1512,149
4,1444,1404,1292,1268,91
0.816 cm ^-1 . NMR (CDCl ₃ ) δ: 0.86 (3H, t, J =
6.5 Hz), 1.41-1.89 (2H, m), 2.
43 (2H, t, J = 6.5Hz), 3.70 (3H,
s), 4.58 (1H, d, J = 13.5Hz), 4.
89 (1H, d, J = 13.5 Hz), 6.63-7.
94 (24H, m), 8.20 (1H, s).

The following compound was obtained in the same manner as in Reference Example 15. Reference Example 16 Methyl 3- [N-propionyl-N- [2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] amino-4-nitrothiophene-2-carboxylate Property: Yellow No Fixed crystal, yield: 70.0% IRν _max (KBr): 3052, 2960, 171
0,1676,1552,1512,1492,144
6,1402,1384,1350,1290,126
6,1096,1190,698 cm ^-1 . NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 6
Hz), 2.03 (2H, q, J = 6Hz), 3.70
(3H, s), 4.59 (1H, d, J = 13.5H
z), 4.89 (1H, d, J = 13.5Hz), 6.
60-7.90 (23H, m), 8.19 (1H,
s).

Reference Example 17 3- [N- [2 '-(1-trityltetrazole-5-
Iyl) biphenyl-4-yl] methyl-N-valeryl]
Methyl amino-4-nitrothiophene-2-carboxylate Property: Yellow amorphous crystal, yield: 32.3% IRν _max (KBr): 2956, 1730, 167
4,1550,1512,1492,1444,140
2,1380,1352,1290,1268,122
2,1192,1102,1088,898,880,
746 cm ^-1 . NMR (CDCl ₃ ) δ: 0.83 (3H, t, J = 6
Hz), 1.10-1.80 (4H, m), 2.03
(2H, t, J = 6Hz), 3.70 (3H, s),
4.59 (1H, d, J = 13.5Hz), 4.89
(1H, d, J = 13.5Hz), 6.73-7.99
(23H, m), 8.20 (1H, s).

Reference Example 18 3- [N-Cyclopropanecarbonyl-N- [2'-
(1-Trityltetrazol-5-yl) biphenyl-
4-yl] methyl] amino-4-nitrothiophene-2
-Methyl carboxylate Property: Yellow amorphous crystal, yield: 63.2% IRν _max (KBr): 3012, 1732, 167
2,1552, 1492, 1474, 1444, 140
8, 1354, 1328, 1292, 1268, 122
4,1190,1100,1030,880,748c
m ^-1 . NMR (CDCl ₃ ) δ: 0.40 to 1.30 (5H,
m), 3.70 (3Hs), 4.63 (1H, d, J =
13.5Hz), 4.93 (1H, d, J = 13.5H
z), 6.60-8.00 (23H, m), 8.19.
(1H, s).

Reference Example 19 Methyl 3- [N-butyryl-N- [4- (1-methoxycarbonyl-1-phenyl) methoxyphenyl] methyl] amino-4-nitrothiophene-2-carboxylate Property: yellow oil , Yield: 53.7% IRν _max (neat): 3016, 1737, 167
4,1554, 1440, 1407, 1374, 135
3,1293,1239,1176,1101,108
6,1047 cm ^-1 . NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7
Hz), 1.40-1.87 (2H, m), 2.01
(2H, t, J = 6.6Hz), 3.64 (3H,
s), 3.72 (3H, s), 4.55 (1H, d, J
= 14.5 Hz), 4.94 (1H, d, J = 14.5)
Hz), 5.58 (1H, s), 6.75 (2H, d,
J = 8.5 Hz), 6.96 (2H, d, J = 8.5H)
z), 7.17-7.65 (4H, m), 8.38 (1
H, s).

Reference Example 20 3- [N-butyryl-N- [5'-chloro-2 '-(1
-Trityltetrazol-5-yl) biphenyl-4-
Methyl] methyl] amino-4-nitrothiophene-2-carboxylate Property: yellow oil, yield: 33.4% IRv _max (neat): 3015, 1731, 167
4,1599,1554,1515,1494,144
6,1404,1386,1353,1329,126
9, 1218, 1197, 1089, 1029, 90
9,828,729 cm ^-1 . NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7
Hz), 1.40-1.85 (2H, m), 2.03
(2H, t, J = 6.5Hz), 3.74 (3H,
s), 4.65 (1H, d, J = 13.6Hz), 4.
87 (1H, d, J = 13.6 Hz), 6.70-7.
57 (21H, m), 7.83 (1H, d, J = 8.1
Hz), 8.23 (1H, s).

Example 1 2-Butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole 60% under argon atmosphere. 2 ml of anhydrous THF was added to 9 mg of sodium hydride, and a solution of 2 ml of anhydrous THF containing 33 mg of 2-butyl-1H-thieno [3,4-d] imidazole was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, then N 2 ml of anhydrous THF containing 122 mg of -trityl-5- [4 '-(bromomethyl) biphenyl-2-yl] tetrazole is added, and the temperature is raised to room temperature and stirred for 18 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture,
Extract with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography to give 2-butyl-1-[[2 'as pale yellow amorphous crystals from the eluate of ethyl acetate-hexane (1: 2). -(1-Trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole (97 mg, yield 8
1.0%). IR v _max (KBr): 3060, 3028, 296
0,2928,2868,1476,1446,140
8, 1390, 1356, 1192, 1162, 102
6,1002,904,880 cm ^-1 . NMR (CDCl ₃ ) δ: 0.92 (3H, t, J =
6.0 Hz), 1.09-2.96 (4H, m), 2.
68 (2H, t, J = 6.0Hg), 4.97 (2H,
s), 6.07 (1H, d, J = 2.0 Hz), 6.7
0-8.02 (24H, m).

The following compound is obtained in the same manner as in Example 1. Example 2 2-Pentyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: pale yellow amorphous, yield Ratio: 79.9% IRv _max (neat): 3060, 2924, 285
6,1598,1528,1510,1490,147
6,1446,1338,1324,1242,118
8,1164,1104,1032,904,880c
m ^-1 . NMR (CDCl ₃ ) δ: 0.73 to 1.03 (3H,
m), 1.06-1.93 (6H, m), 2.67 (2
H, t, J = 6.0 Hz), 4.99 (2H, s),
6.07 (1H, d, J = 2.0 Hz), 6.72-
8.03 (24H, m).

Example 3 2-butyl-1-[[6'-methoxy-2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties : Colorless amorphous crystal, yield: 74.2% IRν _max (KBr): 2950, 1482, 144
9,1431,1410,1392,1353,128
1, 1257, 1206, 1149, 1077, 103
2,999,816 cm ^-1 . NMR (CDCl ₃ ) δ: 0.90 (3H, t, J =
6.0 Hz), 1.12-2.07 (4 H, m), 2.
64 (2H, t, J = 6.0Hz), 3.72 (3H,
s), 4.92 (2H, s), 6.02 (1H, d, J
= 2.0 Hz), 6.70-7.60 (23H, m).

Example 4 2-Butyl-1-[(6'-methoxy-2'-methoxycarbonylbiphenyl-4-yl) methyl] thieno [3,4-d] imidazole Properties: colorless amorphous crystal, yield : 84.4% IRν _max (KBr): 2956, 1725, 149
1,1461, 1434, 1392, 1359, 130
8, 1257, 1224, 1197, 1173, 115
8,1143,1059,846 cm ^-1 . NMR (CDCl ₃ ) δ: 0.92 (3H, t, J =
7.0 Hz), 1.05-2.00 (4H, m), 2.
74 (2H, t, J = 7.0Hz), 3.67 (3H,
s), 5.08 (2H, s), 6.19 (1H, d, J
= 2.0 Hz), 6.92 (1H, d, J = 2.0H
z), 6.80-7.43 (7H, m).

Example 5 2-Butyl-1- [4- [2 '-(1-trityltetrazol-5-yl) phenoxy] benzyl] thieno [3,4-d] imidazole Properties: orange amorphous, yield Ratio: 41.1% IRν _max (KBr): 3448, 2956, 292
6,1503,1476,1449,1239,74
4,696 cm ^-1 . NMR (CDCl ₃ ) δ: 0.92 (3H, t, J =
6.5 Hz), 1.13-2.00 (4H, m), 2.
70 (2H, t, J = 6.5Hz), 5.00 (2H,
s), 6.11 (1H, d, J = 2.5Hz), 6.6
8 (2H, d, J = 8.5 Hz), 6.80-7.48
(21H, m), 8.00-8.20 (1H, m).

Example 6 2-Butyl-1- [4- (2-methoxycarbonylphenoxy) benzyl] thieno [3,4-d] imidazole Property: pale yellow oily substance, yield: 59.7% IRν _max ( neat): 2956, 1731, 160
2,1509, 1485, 1452, 1410, 139
2,1299,1275,1239,1164,112
5,1083,729 cm ^-1 . NMR (CDCl ₃ ) δ: 0.96 (3H, t, J =
6.0 Hz), 1.10-1.97 (4H, m), 2.
72 (2H, t, J = 7.0Hz), 3.74 (3H,
s), 5.01 (2H, s), 6.17 (1H, d, J
= 2.0 Hz), 6.70-7.54 (8H, m),
7.75-7.94 (1H, m).

Example 7 2-Butyl-1-[(2'-nitrobiphenyl-4-yl) methyl] thieno [3,4-d] imidazole Property: orange oily substance, yield: 98.8% IRν _max (Neat): 2956, 2926, 286
6,1527, 1479, 1443, 1410, 138
9,1356,1107,852 cm ^-1 . NMR (CDCl ₃ ) δ: 0.92 (3H, t, J =
6.5 Hz), 1.05-2.00 (4H, m), 2.
73 (2H, t, J = 6.5Hz), 5.10 (2H,
s), 6.21 (1H, d, J = 2.0 Hz), 6.9.
4 (1H, d, J = 2.0 Hz), 7.00-7.70
(7H, m), 7.70-7.92 (1H, m).

Example 8 2-Butyl-1-[(2'-aminobiphenyl-4-yl) methyl] thieno [3,4-d] imidazole 2-butyl-1-[(2'-nitrobiphenyl-4) -Yl) methyl] thieno [3,4-d] imidazole 49
Iron powder 24 in 25 ml of methanol solution containing 1.5 mg
Add 5.7 mg and 0.5 ml of acetic acid and heat to reflux for 5 hours. The methanol of the reaction mixture is distilled off under reduced pressure, and the resulting residue is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 2-butyl-1-[(2'-aminobiphenyl-
4-yl) methyl] thieno [3,4-d] imidazole (428.8 mg, yield 94.5%) is obtained. IRv _max (neat): 3460, 3370, 295
6,2926,2866,1617,1530,148
5,1452,1410,1392,1350,114
3,1104,729,747 cm ^-1 . NMR (CDCl ₃ ) δ: 0.92 (3H, t, J =
6.5 Hz), 1.10-2.13 (4H, m), 2.
75 (2H, t, J = 6.5Hz), 5.11 (2H,
s), 6.25 (1H, d, J = 2Hz), 6.50-
7.50 (8H, m), 6.96 (1H, d, J = 2H
z).

Example 9 2-Butyl-1-[(2'-carboxy-6'-methoxybiphenyl-4-yl) methyl] thieno [3,4-
d] imidazole 2-butyl-1-[(6'-methoxy-2'-methoxycarbonylbiphenyl-4-yl) methyl] thieno [3,4-d] imidazole 183.1 mg in a solution of 6 ml of methanol under ice cooling 10 % Aqueous sodium hydroxide solution, and the mixture is stirred at room temperature overnight at 50 ° C. for 6 hours. The solvent of the reaction mixture is distilled off under reduced pressure, water is added to the residue and the mixture is washed with ethyl acetate. The aqueous layer is made weakly acidic by adding 2N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer is washed with saturated brine and dried over anhydrous magnesium sulfate. When ethyl acetate was distilled off under reduced pressure, 2-butyl-1-[(2'-carboxy-6'-methoxybiphenyl-4-yl) methyl] thieno [3,4
-D] imidazole (143.5 mg, yield 81.0
%). IRν _max (KBr): 2950, 2866, 169
2,1575,1521,1461,1437,140
7,1296,1251,1188,1155,113
1,1110,1086,1053,1002,94
2,900,855,837,813,762,75
0,732 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.92 (3
H, t, J = 6.5 Hz), 1.20-1.97 (4
H, m), 2.76 (2H, t, J = 6.5 Hz),
3.71 (3H, s), 5.13 (2H, s), 6.2
8 (1H, d, J = 2Hz), 6.91 (1H, d, J
= 2 Hz), 6.97-7.47 (7H, m).

Example 10 2-Butyl-1- [4- (2-carboxyphenoxy)
Benzyl] thieno [3,4-d] imidazole Properties: pale yellow powder, melting point: 157-158 ° C, yield: 8
9.3% IRν _max (KBr): 2956, 1707, 160
2,1509, 1482, 1452, 1401,135
9,1236,1164,1134,1080,87
9,777 cm ^-1 . NMR (CDCl ₃ ) δ: 0.84 (3H, t, J =
6.5 Hz), 1.10-1.90 (4H, m), 2.
73 (2H, t, J = 7.0Hz), 5.02 (2H,
s), 6.21 (1H, d, J = 2.0 Hz), 6.7.
0-7.57 (8H, m), 8.00 (1H, d, J =
8.0 Hz).

Example 11 2-Butyl-4-methyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole and 2 -(1-
Methylbutyl) -1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole 2-butyl-1-[[2 ′-(1-
Trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole 197
Anhydrous THF 6 ml was added to mg and cooled to -78 ° C.
0.53 of 1.7 molar t-butyllithium pentane solution
After adding 30 ml and stirring for 30 minutes, 75 μl of methyl iodide
Is added and the mixture is stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and 2-butyl-4-methyl-1- [as pale yellow amorphous crystals was obtained from the elution part of ethyl acetate-hexane (1: 2). [2 '-(1-Trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-
d] imidazole (88.8 mg, yield 44.2%) and 2- (1-methylbutyl) -1 as a colorless candy.
-[[2 '-(1-Trityltetrazol-5-yl)
Biphenyl-4-yl] methyl] thieno [3,4-d]
Imidazole (38.7 mg, yield 19.3%) is obtained.

2-butyl-4-methyl-1-[[2'-
(1-Trityltetrazol-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazole: IRv _max (KBr): 2956, 2924,286
0, 1506, 1446, 1408, 1384, 135
6,1192,746 cm ^-1 . NMR (CDCl ₃ ) δ: 0.80 (3H, t, J =
6.0 Hz), 1.06-1.85 (4H, m), 2.
62 (3H, s), 2.66 (2H, t, J = 6.0H
z), 4.93 (2H, s), 5.79 (1H, s),
6.74-8.04 (23H, m). 2- (1-Methylbutyl) -1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl]
Methyl] thieno [3,4-d] imidazole: IRν _max (neat): 3060, 2960, 292
3,2868, 1528, 1512, 1490, 147
6,1448,1430,1320,1240,120
0,1004,816 cm ^-1 . NMR (CDCl ₃ ) δ: 0.83 (3H, t, J =
6.0 Hz), 1.03-2.02 (4 H, m), 1.
30 (3H, t, J = 6.0Hz), 2.62-2.9.
0 (1H, m), 5.01 (1H, s), 6.03 (1
H, d, J = 2.0 Hz), 6.62-8.00 (24
H, m).

Example 12 2- (1-methylbutyl) -4-methyl-1-[[2 '
-(1-Trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole 2-butyl-4-methyl-1- under an argon atmosphere.
To [[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole (102 mg) was added anhydrous THF (4 ml), and -7
After cooling to 8 ° C. and adding 0.26 ml of 1.7 mol t-butyllithium pentane solution and stirring for 30 minutes, 38 μl of methyl iodide is added and stirred for 1 hour at the same temperature. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate.
Ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was subjected to silica gel column chromatography to give 2- (1- as a colorless candy-like substance from the elution part of ethyl acetate-hexane (1: 3).
Methylbutyl) -4-methyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole (47
mg, yield 45.3%). IRν _max (neat): 3060, 3028, 296
0,2928,2868,1494,1446,141
0, 1356, 1318, 1216, 1198, 115
4,1102,908,732 cm ^-1 . NMR (CDCl ₃ ) δ: 0.81 (3H, t, J =
6.0 Hz), 1.28-1.92 (4H, m), 1.
28 (3H, d, J = 6.0Hz), 2.42-2.8
4 (1H, m), 2.61 (3H, s), 4.94 (2
H, s), 5.79 (1H, s), 6.71-7.94.
(23H, m).

Example 13 2-Butyl-4-formyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl]
Methyl] thieno [3,4-d] imidazole Under an argon atmosphere, 2-butyl-1-[[2 '-(1-
Trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole 205
Anhydrous THF (6.3 ml) was added to the solution (mg), cooled to -78 ° C, and a 1.7 mol t-butyllithium pentane solution (0.1 mol) was added.
After adding 48 ml and stirring for 30 minutes, 72.6 μl of dimethylformamide was added. The reaction mixture solution is stirred at −78 ° C. for 2 hours, then gradually warmed to −10 ° C. and stirred for 1 hour, then saturated ammonium chloride aqueous solution is added to the reaction mixture solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was subjected to silica gel column chromatography, and 2-butyl-4-formyl-1- as a pale yellow candy was obtained from the elution part of ethyl acetate-hexane (1: 2). [[2'-
(1-Trityltetrazol-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazole (114 mg, 53.3% yield) is obtained. IRν _max (neat): 2956, 1650, 152
7, 1479, 1449, 1395, 1245, 115
2,1095,909 cm ^-1 . NMR (CDCl ₃ ) δ: 0.95 (3H, t, J =
6.0 Hz), 1.10-1.93 (4H, m), 2.
81 (2H, t, J = 6.0Hz), 5.04 (2H,
s), 6.50 (1H, s), 6.75-8.04 (2
3H, m), 10.16 (1H, s).

Example 14 E-3- [2-butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole- 4-yl]-
Ethyl 2-propenoate Under an argon atmosphere, 3 ml of anhydrous THF containing 122 mg of triethylphosphonoacetate was added dropwise to a suspension of 16 ml of 60% sodium hydride in 2 ml of anhydrous THF at room temperature, and the mixture was stirred at the same temperature for 1 hour. Add 2 to the reaction mixture under ice cooling.
4 ml of anhydrous THF containing 187 mg of -butyl-4-formyl-1-[[2 '-(1-trityltetrazol-5] yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole was added 1 Stir for hours. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate.
Ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was subjected to silica gel column chromatography to give E-3 as pale yellow amorphous crystals from the elution part of ethyl acetate-hexane (1: 2).
-[2-Butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-4-yl] -2-propenoic acid Ethyl (153 mg, yield 74.4%) is obtained. IR ν _max (neat): 1694, 1610, 148
2,1448,1390,1312,1262,117
8,1146,908,730 cm ^-1 . NMR (CDCl ₃ ) δ: 0.93 (3H, t, J =
6.0 Hz), 1.07-1.81 (4H, m), 1.
32 (3H, t, J = 6.0 Hz), 2.73 (2H,
t, J = 6.0 Hz), 4.23 (2H, t, J = 6.
0 Hz), 4.97 (2H, s), 6.10 (1H,
s), 6.57 (1H, d, J = 13.0Hz), 6.
74-8.12 (24H, m).

Example 15 E-3- [2-Butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole- 4-yl]-
Methyl 2- (2-thienyl) methyl-2-propenoate Under an argon atmosphere, a solution of 3 ml of anhydrous THF and 0.13 ml of diisopropylamine is cooled to -78 ° C, and then 1.5.
0.6 ml of a 5 mol n-butyllithium hexane solution was added dropwise and stirred at the same temperature for 30 minutes, and then 3- (2-thienyl)
3 ml of anhydrous THF containing 206 mg of methyl propanoate
Was added and stirred at the same temperature for 40 minutes, and then 2-butyl-4-formyl-1-[[2 '-(1-trityltetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
4-d] Anhydrous THF3 containing 144 mg of imidazole
Add ml and stir at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
From the elution part of 2), E-3- [2-butyl-1-[[2 '-(1-trityltetrazole-5-
Il) biphenyl-4-yl] methyl] thieno [3,4
Methyl -d] imidazol-4-yl] -2- (2-thienyl) methyl-2-propenoate (85 mg, yield 4
8.3%). IR ν _max (neat): 3012, 2956, 173
4,1648,1492,1474,1446,141
0, 1390, 1356, 1324, 1258, 121
4,1160, 1094, 1030, 1004 cm ^-1 . NMR (CDCl ₃ ) δ: 0.90 (3H, t, J =
6.0 Hz), 1.14-1.95 (4H, m), 2.
43-2.84 (2H, m), 3.16-3.60 (2
H, m), 3.56 (3H, s), 4.92 (2H,
s), 5.14-5.60 (1H, m), 5.98 (1
H, s), 6.57 (1H, d, J = 13.0Hz),
6.62-8.02 (26H, m).

Example 16 2-Butyl-4-hydroxymethyl-1-[[2'-
(1-Trityltetrazol-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazole Under an argon atmosphere, 2-butyl-4-formyl-1-
114 mg of [[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole was added to 5 ml of methanol and THF.
Dissolved in 4 ml, sodium borohydride 12.8 mg
Is added under ice cooling and stirred for 30 minutes. Acetone is added to the reaction mixture solution, the solvent is evaporated under reduced pressure, and the resulting residue is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to give 2-butyl-4-hydroxymethyl-1-[[2'-
(1-Trityltetrazol-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazole (117 mg, 100% yield) is obtained. IR ν _max (neat): 3300, 3064, 296
0, 2932, 2872, 1496, 1474, 144
6,1430,1406,1390,1358,103
2,1018,1004,908,880 cm ^-1 . NMR (CDCl ₃ ) δ: 0.89 (3H, t, J =
6.0 Hz), 1.08-1.87 (4H, m), 2.
67 (2H, t, J = 6.0 Hz), 3.04-3.3
7 (1H, bs), 4.96, 5.04 (each2
H, s), 6.0 (1H, s), 6.67-8.01
(23H, m).

Example 17 2-Butyl-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4-d] imidazole 2-butyl-4-methyl-[[2 '
43 mg of-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole to 43 mg of dioxane and 4 ml of 50% acetic acid.
Is added and the mixture is stirred at 60 ° C. for 2 hours. Under ice-cooling, 10% aqueous sodium hydroxide solution was added to the reaction mixture solution to make it alkaline, and the aqueous layer was washed with ether, and then the aqueous layer was washed with 2N-hydrochloric acid.
Adjust to H5 and extract with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and the ethyl acetate layer is dried over anhydrous magnesium sulfate. When ethyl acetate was distilled off under reduced pressure, crude crystals were obtained and recrystallized from ether-hexane to give 2-butyl-4 as a pale yellow powder having a melting point of 119-126 ° C.
-Methyl-1-[[2 '-(1H-tetrazole-5-
Il) biphenyl-4-yl] methyl] thieno [3,4
-D] imidazole (26.3 mg, yield 95.3%)
To get IRν _max (KBr): 2956, 1504, 141
0,968,848 cm ^-1 . NMR (CDCl ₃ ) δ: 0.81 (3H, t, J =
6.0 Hz), 1.04-1.76 (4H, m), 2.
16 (3H, s), 4.98 (2H, s), 5.98
(1H, s), 6.78-7.98 (8H, m).

The following compound is obtained in the same manner as in Example 17. Example 18 2-propyl-1-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: colorless powder, melting point: 118-124 ° C, yield: 4
2.8% IRν _max (KBr): 2964, 1580, 156
0,1540,1524,1510,1476,145
8, 1450, 1400, 1354, 1200, 114
8 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.02
(3H, t, J = 6.0 Hz), 1.86 (2H, qu
in, J = 6.0 Hz), 2.66 (2H, t, J =
6.0 Hz), 5.06 (2H, s), 6.25 (1
H, d, J = 2.0 Hz, 6.81 (1H, d, J =
2.0 Hz), 6.86-7.79 (8H, m).

Example 19 2-Pentyl-1-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: colorless powder, melting point: 193.5-196 ° C, yield:
76.7% IRν _max (KBr): 2952, 2932, 286
4,1524,1478,1452,1422,140
0, 1346, 1146, 1108, 1006, 97
4,810 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.71-
1.02 (3H, m), 1.08-1.93 (6H,
m), 2.69 (2H, t, J = 6.0Hz), 5.0
9 (2H, s), 6.27, 6.78 (each1H,
d, J = 2.0 Hz), 6.92-7.83 (8H,
m).

Example 20 2- (1-methylbutyl) -1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: pale Yellow powder, melting point: 122-128 ° C, yield: 9
4.7% IRν _max (KBr): 3112, 3060, 295
6,2928,2868,1406,765 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.70-
0.93 (3H, m), 1.06 (3H, d, J = 6.
0 Hz), 1.13-1.84 (4H, m), 2.46
-2.83 (1H, m), 5.10 (2H, s), 6.
10, 6.24 (each 1H, d, J = 2.0H
z), 6.67-7.89 (8H, m).

Example 21 2- (1-methylbutyl) -4-methyl-1-[[2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Ilyl] methyl] thieno [3,4-d] imidazole Properties: pale yellow powder, melting point: 131-138 ° C, yield: 7
2.5% IRν _max (KBr): 2960, 2868, 149
8, 1458, 1408, 1358, 1322, 121
6,1152,1106,1004,838 cm ^-1 . NMR (CDCl ₃ ) δ: 0.93 (3H, t, J =
6.0 Hz), 1.10 (3H, d, J = 6.5H)
z), 1.10-1.93 (4H, m), 2.42 (3
H, s), 2.53 to 2.96 (1H, m), 5.10.
(2H, s), 6.04 (1H, s), 6.95-8.
06 (8H, m).

Example 22 2-Butyl-4-formyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: colorless Powder, melting point: 163-170 ° C, yield: 7
9.1% IRν _max (KBr): 3440, 2960, 164
8,1522,1476,1404,1154,110
4 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.96
(3H, t, J = 6.0 Hz), 1.07-1.80
(4H, m), 2.86 (2H, t, J = 6.0H
z), 5.15 (2H, s), 6.71 (1H, s),
6.96-7.86 (8H, m), 10.50 (1H,
s).

Example 23 2-butyl-4-hydroxymethyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: colorless powder, melting point: 168-180 ° C (decomposition), yield: 85.5% IRν _max (KBr): 3416, 3112, 295
6,2932,2868,1500,1458,140
8, 1358, 1218, 1101, 1066, 100
6 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.93
(3H, t, J = 6.0 Hz), 1.10-1.93
(4H, m), 2.78 (2H, t, J = 6.0H
z), 4.96, 5.12 (each2H, s), 6.
23 (1H, s), 6.86-7.78 (8H, m).

Example 24 2-Butyl-1-[[6'-methoxy-2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: colorless powder, melting point: 189-190 ° C (decomposition), yield: 71.9% IRν _max (KBr) : 2956, 2866, 152
4,1470,1443,1404,1377,125
4,1080,1044,999,816 cm ^-1 . NMR (CDCl ₃ ) δ: 0.90 (3H, t, J =
6.0 Hz), 1.05-1.90 (4H, m), 2.
68 (2H, t, J = 6.5Hz), 3.85 (3H,
s), 5.07 (2H, s), 6.21 (1H, d, J
= 2.0 Hz), 6.81 (1H, bs), 6.90-
7.60 (7H, m).

Example 25 2-Butyl-1- [4- [2 '-(1H-tetrazol-5-yl) phenoxy] benzyl] thieno [3,4-
d] Imidazole Properties: pale orange powder, melting point: 110-112 ° C, yield: 9
9.7% IRν _max (KBr): 2956, 2926, 286
6,1506,1479,1461,1401,123
3,1164,1107,747 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.90 (3
H, t, J = 6.5 Hz), 1.03-1.93 (4
H, m), 2.72 (2H, t, J = 6.5 Hz),
5.07 (2H, s), 6.23 (1H, d, J = 2.
0 Hz), 6.70-7.50 (8H, m), 8.20
(1H, d, J = 8.0 Hz).

Example 26 E-3- [2-Butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4 -Yl] -2-
(2-thienyl) -2-propenoic acid E-3- [2-butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4- d] imidazol-4-yl]-
Methyl 2- (2-thienyl) -2-propenoate 116m
To g, 4 ml of methanol, 4 ml of THF and 2 ml of 10% sodium hydroxide aqueous solution are added, and the mixture is stirred at 50 ° C. for 8 hours and at room temperature overnight. After water was added to the reaction mixture and the mixture was washed with ether, the aqueous layer was adjusted to about pH 5 with 2N-hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried to give E-3- [2 -Butyl-1-[[2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Il] methyl] thieno [3,4-d] imidazole-4
-Yl] -2- (2-thienyl) -2-propenoic acid (4
4 mg, yield 54.1%) is obtained. IRν _max (KBr): 3432, 3112, 296
0,2932,1638,1507,1476,146
0,1406,1356,1254,1200,110
2,1068,1007 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.69-
1.06 (3H, m), 1.13-1.93 (4H,
m), 2.79 (2H, t, J = 6.0Hz), 3.1
6-3.52 (2H, m), 5.07 (2H, s),
5.43-7.76 (13H, m).

The following compound was obtained in the same manner as in Example 26. Example 27 E-3- [2-Butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-4-yl] -2-Propenoic acid Properties: pale yellow powder, melting point: 151-155 ° C, yield: 6
0.1% IRν _max (KBr): 3454, 3070, 296
2,1680, 1614, 1482, 1404, 133
8,1293, 1194, 1164, 1104 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.95
(3H, t, J = 6.0 Hz), 1.08-2.05
(4H, m), 2.82 (2H, t, J = 6.0H
z), 5.11 (2H, s), 6.37 (1H, s),
6.49 (1H, d, J = 11.0 Hz), 6.87-
8.07 (9H, m).

Example 28 Methyl 2-butyl-1H-thieno [3,4-d] imidazole-4-carboxylate 2-butyl-1H-thieno [3,4] under an argon atmosphere.
-D] 181 mg of imidazole was added to anhydrous THF-HMPA.
It was dissolved in a mixed solvent of (5: 1), and 2.33 ml of a 1.55 mol n-butyllithium hexane solution was added dropwise at -78 ° C and stirred. Carbon dioxide was introduced into the reaction mixture cooled to −78 ° C. while warming to room temperature, and stirred for 1 hour.
Water was added to the reaction mixture and washed with ether, and the aqueous layer was washed with 2N-
The pH is adjusted to 3 to 4 with hydrochloric acid, extraction is performed with ethyl acetate, an excess ether solution of diazomethane is added, and the organic layer is dried over anhydrous magnesium sulfate. The organic solvent was evaporated under reduced pressure, and the obtained yellow oil was subjected to silica gel column chromatography, ethyl acetate-hexane (2:
2-butyl-1H as a pale yellow oily substance from the elution part of 3)
-Methyl thieno [3,4-d] imidazole-4-carboxylate (96 mg, yield 40.3%) is obtained. IRν _max (neat): 2956, 1702, 154
4,1438,1390,1192,1168,114
6,732 cm ^-1 . NMR (CDCl ₃ ) δ: 0.90 (3H, t, J =
7.0 Hz), 1.13-1.57 (2H, m), 1.
57-2.00 (2H, t, J = 7.5Hz), 3.8
6 (3H, s), 7.22 (1H, s).

The following compound is obtained in the same manner as in Example 1. Example 29 Methyl 2-butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4-carboxylate Property: colorless Amorphous crystal, yield: 73.4% IRν _max (neat): 2956, 1700, 148
0,1448,1434,1392,1164,111
6,910,732 cm ^-1 . NMR (CDCl ₃ ) δ: 0.90 (3H, t, J =
7.0 Hz), 1.10-1.57 (2H, m), 1.
57-2.00 (2H, m), 2.80 (2H, t, J
= 7.5 Hz), 3.95 (3H, s), 5.00 (2
H, s), 6.30 (1H, s), 6.70-7.70.
(22H, m), 7.73-8.05 (1H, m).

Example 30 2-Butyl-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
Methyl 4-d] imidazole-4-carboxylate 2-butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole- Methyl 4-carboxylate 6
Dioxane 1 ml and 50% acetic acid aqueous solution 1.8 ml were added to 7.7 mg, and the mixture was stirred at 60 ° C. for 1 hour. below freezing,
The reaction mixture was adjusted to pH 11 with 10% sodium hydroxide and washed with ether. After adjusting the pH to 5 by adding 2N-hydrochloric acid to the aqueous layer, ethyl acetate-methanol (3:
It was extracted with the mixed solution of 1). The extract was washed successively with H ₂ O and saturated brine, and dried over anhydrous magnesium sulfate. The extract was evaporated under reduced pressure, and the obtained crystalline residue was crystallized from hexane-ether to give 2-butyl-1-
Methyl [[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4-carboxylate (39.6 mg, yield 8)
8.5%). IRν _max (KBr): 3404, 2956, 169
8, 1478, 1434, 1404, 1320, 117
0,764 cm ^-1 . NMR (CD ₃ OD) δ: 0.95 (3H, t, J =
7.0 Hz), 1.10-2.00 (4H, m), 2.
93 (2H, t, J = 7.5 Hz), 3.91 (3H,
s), 5.35 (2H, s), 6.97 (1H, s),
7.18 (4H, s), 7.35-7.86 (5H,
m).

Example 31 2-butyl-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
4-d] imidazole-4-carboxylic acid 2-butyl-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
4-d] imidazole-4-carboxylate methyl 39.6
5 mg of methanol and 2 ml of 10% aqueous sodium hydroxide solution were added to mg, and the mixture was stirred at room temperature for 18 hours. After adding water to the reaction mixture and washing with pentane, 2N-hydrochloric acid was added to the aqueous layer to adjust the pH to 3 to 4, and the mixture was extracted with a mixed solution of ethyl acetate-methanol (3: 1). The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The extract was distilled off under reduced pressure, and the obtained crystalline residue was crystallized with hexane-ether and had a melting point of 157-163 ° C.
As a colorless powder of 2-butyl-1-[[2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-4-carboxylic acid (23.5 mg, yield 61.2%) is obtained. Also, 2
Methyl -butyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4-carboxylate was used in the method of Example 26. The above compound is obtained in a similar manner. IRv _max (KBr): 2960, 1686, 152
9, 1480, 1408, 1362, 1174, 111
6,776,762 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 0.93
(3H, t, J = 7.0Hz), 1.20-2.00
(4H, m), 2.83 (2H, t, J = 7.5H
z), 5.16 (2H, s), 6.57 (1H, s),
7.10 (4H, s), 7.30-7.80 (5H,
m).

Example 32 2-N- [2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] thieno [3,4-d] imidazol-4-yl] ] Carbamoyl] -2-methylphenylphenylpropionate Under an argon atmosphere, 12.7 mg of phenylalanine methyl ester hydrochloride and 2-butyl-1-[[2'-
(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-4-
24 mg of carboxylic acid was suspended in methylene chloride, 8 μl of triethylamine was added, and the mixture was stirred at room temperature for 15 minutes. 1- (3-dimethylaminopropyl) was added to the reaction mixture under ice cooling.
13 mg of -3-ethylcarbodiimide hydrochloride was added, the temperature was gradually raised to room temperature, and the mixture was stirred for 13 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with a 10% aqueous citric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The yellow oily substance obtained by distilling off ethyl acetate under reduced pressure was subjected to silica gel column chromatography, and 2-N- [2-butyl-1-
[[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] thieno [3,4-d] imidazol-4
Methyl -yl] carbamoyl] -2-phenylpropionate (13.0 mg, yield 40.1%) is obtained. IRν _max (neat): 2968, 1732, 162
8, 1534, 1482, 1396, 1154, 91
0,732 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.97 (3
H, t, J = 7.0 Hz), 1.20-2.00 (4
H, m), 2.79 (2H, t, J = 7.5 Hz),
3.23 (2H, d, J = 6.0 Hz), 3.70 (3
H, s), 4.84-5.15 (1H, m), 5.11.
(2H, s), 6.42 (1H, s), 7.00-8.
24 (4H, m), 7.10 (4H, s), 7.25
(5H, s).

The following compound is obtained by a method similar to that in Example 26. Example 33 2-N- [2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] thieno [3,4-d] imidazol-4-yl] carbamoyl] 2-Phenylpropionic acid Property: Light yellow amorphous crystal, yield: 62.9% IRν _max (neat): 2924, 1720, 162
4,1526,1476,1398,1180,758
cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.96 (3
H, t, J = 7.0 Hz), 1.13-2.30 (4
H, m), 2.75 (2H, t, J = 7.5 Hz),
3.10-3.60 (2H, m), 4.70-5.30
(1H, m), 5.08 (2H, s), 6.40 (1
H, s), 6.90-8.10 (5H, m).

The following compound is obtained in the same manner as in Example 1. Example 34 2-Methylthio-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Property: pale yellow amorphous, yield Ratio: 63.1% IRν _max (KBr): 3060, 2924, 149
2,1472,1448,1428,1410,134
2,1312,1240,1188,1156,103
0,1002,746 cm ^-1 . NMR (CDCl ₃ ) δ: 2.71 (3H, s), 4.
91 (2H, s), 6.01 (1H, d, J = 2.0H
z), 6.67-8.02 (24H, m).

Example 35 2-Ethylthio-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Property: pale yellow amorphous Crystal, yield: 71.6% IRv _max (KBr): 3060, 2928, 144
6,1430,1410,1342,908,730c
m ^-1 . NMR (CDCl ₃ ) δ: 1.43 (3H, t, J =
6.0 Hz), 3.30 (2H, q, J = 6.0H
z), 4.90 (2H, s), 6.02 (1H, d, J
= 2.0 Hz), 6.72-8.00 (24H, m).

Example 36 2-Propylthio-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4-d] imidazole Properties: Light yellow candy, yield: 72.2% IRv _max (neat): 3060, 3028, 296
4,2928,1492,1446,1430,141
0,1372,1288,1242,1190,115
6,1044,748 cm ^-1 . NMR (CDCl ₃ ) δ: 1.03 (3H, t, J =
6.0 Hz), 1.78 (2H, quin, J = 6.0)
Hz), 3.31 (2H, t, J = 6.0Hz), 4.
93 (2H, s), 6.00 (1H, J = 6.0H
z), 6.72-8.03 (24H, m).

[0095]

The following compounds are obtained as in Example 17. Example 38 2-Methylthio-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Property: colorless powder, melting point: 126-130 ℃ (decomposition), yield: 36.6% IRν _max (KBr): 1450,1428,134
2,1312,758 cm ^-1 . NMR (CDCl ₃ + DMSO-d ₆ ) δ: 2.72
(3H, s), 5.03 (2H, s), 6.23 (1
H, bs), 6.74-7.83 (9H, m).

Example 39 2-Ethylthio-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] thieno [3,4-
d] Imidazole Properties: Light brown powder, melting point: 108-114 ° C, yield: 8
6.4% IRν _max (KBr): 3118, 2968, 292
6,1479,1449,1428,1341,131
1,1263,1197,1158,1110,105
9,975,816 cm ^-1 . NMR (CDCl ₃ ) δ: 1.34 (3H, t, J =
6.0 Hz), 3.12 (2H, g, J = 6.0H
z), 5.06 (2H, s), 6.08-6.32 (2
H, m), 6.86-8.06 (8H, m).

Example 40 2-propylthio-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: pale yellow powder, melting point : 161-165 ° C (decomposition),
Yield: 56.2% IRv _max (KBr): 3112, 2964, 292.
8, 1480, 1448, 1428, 1410, 138
8, 1364, 1346, 1312, 1194, 116
0,976,812,802 cm ^-1 . NMR (CDCl ₃ ) δ: 1.00 (3H, t, J =
6.0 Hz), 1.79 (2H, quin, J = 6.0)
Hz), 3.10 (2H, t, J = 6.0 Hz), 5.
06 (2H, s), 6.19, 6.32 (each1
H, d, J = 2.0 Hz), 6.86-8.09 (8
H, m).

Example 41 2-Butylthio-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole Properties: pale yellow powder, melting point 176-179 ° C (decomposition),
Yield: 60.1% IRν _max (KBr): 2956, 2926, 286
6,1482,1449,1428,1410,135
9, 1308, 1197, 1158, 1104, 97
8,753 cm ^-1 . _{NMR (CDCl 3) δ: 0.76-1.02} (3H,
m), 1.06-1.83 (4H, m), 3.08 (2
H, t, J = 6.0 Hz), 5.03 (2H, s),
6.08-6.26 (2H, m), 6.76-8.01
(8H, m).

Example 42 2-Propyl-1-[[2 '-(1H-tetrazole-
Methyl 5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate 3- [N-[(2 '-(1-trityltetrazole-5
-Yl) Biphenyl-4-yl] methyl-N-butyryl] amino-4-nitrothiophene-2-carboxylate methyl 346 mg to methanol 9 ml and THF 6 ml.
Add and dissolve, and add 5.4 ml of concentrated hydrochloric acid under ice cooling and add 50 ° C.
Heat to about 10 mg of 174 mg of tin and add 10
After stirring for 1 minute, the reaction mixture was ice-cooled, the remaining tin was added little by little, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture is poured into ice water, saturated aqueous sodium hydrogen carbonate is added to adjust the pH to 7 to 8, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting pale yellow oily matter was added with 12 ml of methanol.
, P-toluenesulfonic acid monohydrate 194 mg
Is added and the mixture is stirred at room temperature for 1 hour, then heated to 60 ° C. and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice cooling to adjust the pH to 6-
Adjust to 7 and extract with chloroform. The chloroform layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The crude crystals obtained by distilling off chloroform under reduced pressure were subjected to silica gel column chromatography, and 2-propyl was obtained as a pale yellow powder having a melting point of 228 to 230 ° C. (decomposition) from the elution part of chloroform-methanol (100: 1 to 100: 5). -1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-
d] Methyl imidazole-6-carboxylate (138 m
g, yield 65.1%). IRν _max (KBr): 2950, 1706, 153
4, 1450, 1392, 1336, 1316, 124
6,1232,1196,1116,1086,105
4,910 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.90 (3
H, t, J = 6.5 Hz), 1.54-1.94 (2
H, m), 2.66 (2H, t, J = 6.5 Hz),
3.80 (3H, s), 5.80 (2H, s), 6.9
1-7.84 (9H, m).

The following compound is obtained as in Example 42. Example 43 Methyl 2-ethylthio-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate Property: yellow powder , Melting point: 195-197 ° C., yield: 3
4.3% IRν _max (KBr): 3432, 2980, 259
6,1696,1596,1538,1484,143
8, 1392, 1358, 1336, 1314, 124
4,1194,1118,1050,904,864,
760 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 1.29 (3
H, t, J = 6.0 Hz), 2.70 (2H, q, J =
6.0 Hz), 3.80 (3H, s), 5.80 (2
H, s), 6.80-7.89 (10H, m).

Example 44 2-Butyl-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
4-d] Methyl imidazole-6-carboxylate Properties: yellow powder, melting point: 203-206 ° C, yield: 5
5.9% IRν _max (KBr): 2956, 2868, 169
8,1596,1536,1482,1438,139
2,1336, 1320, 1244, 1188, 111
6,1086,910,760 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.85 (3
H, t, J = 6.0 Hz), 1.10-1.90 (4
H, m), 2.63 (2H, t, J = 6.0 Hz),
3.73 (3H, s), 5.73 (2H, s), 6.8
0-7.80 (10H, m).

Example 45 Methyl 2-cyclopropyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate Property: yellow powder, melting point: 168-170 ° C, yield: 4
4.9% IRν _max (KBr): 3016, 1698, 160
4,1544,1480,1444,1410,131
8, 1248, 1208, 1180, 1116, 104
8,856,758 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.80-1.
45 (4H, m), 1.60-1.90 (1H, m),
3.80 (3H, s), 5.93 (1H, s), 6.9
0-8.00 (10H, m).

Example 46 Methyl 1-[[4- (1-methoxycarbonyl-1-phenyl) methoxyphenyl] methyl] -2-propylthieno [3,4-d] imidazole-6-carboxylate Property: pale yellow Oil, yield: 70.6% IRv _max (neat): 1755, 1698, 151
2,1440,1335,1236,1188,111
3,1050,909,729 cm ^-1 . NMR (CDCl ₃ ) δ: 0.95 (3H, t, J =
7.0 Hz), 1.53-2.00 (2H, m), 2.
61 (2H, t, J = 7.0Hz), 3.69 (3H,
s), 3.76 (3H, s), 5.58 (1H, s),
5.71 (2H, s), 6.86-7.10 (4H,
m), 7.17-7.63 (5H, m).

Example 47 2-Propyl-1-[[5'-chloro-2 '-(1H-
Methyl tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate Properties: pale yellow amorphous, yield: 69.6% IRν _max (KBr): 2950, 1700, 160
0,1518,1418,1385,1330,122
8, 1188, 1115, 1050 cm ^-1 . NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.6 Hz), 1.33-1.90 (2H, m), 2.
43 (2H, t, J = 6.8Hz), 3.74 (3H,
s), 5.70 (2H, s), 6.70-7.62 (7)
H, m), 7.85 (1H, d, J = 7.9 Hz).

Example 48 2-Propyl-1-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid 2-propyl-1-[[2 '-(1H-tetrazole-
Methyl 5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate 1
To 38 mg, 18 ml of methanol and 15 ml of 10% aqueous sodium hydroxide solution are added, and the mixture is stirred at room temperature for 15 hours.
Water is added to the reaction mixture and the mixture is washed with ether. The pH of the aqueous layer is adjusted to 6 with 2N-hydrochloric acid under ice cooling, and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine,
Dry over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ether-hexane to give 2 as a pale yellow powder having a melting point of 218-220 ° C (decomposition).
-Propyl-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
4-d] imidazole-6-carboxylic acid (125 mg,
Yield 93.3%) is obtained. IR v _max (KBr): 2972, 1686, 160
6,1518,1476,1466,1450,141
0, 1368, 1236, 1192, 936, 776c
m ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 1.00 (3
H, t, J = 6.5 Hz), 1.51-1.93 (2
H, m), 2.66 (2H, t, J = 6.5 Hz),
5.83 (2H, s), 6.92-7.78 (9H,
m).

The following compound is obtained as in Example 48. Example 49 2-Ethyl-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
4-d] imidazole-6-carboxylic acid Properties: yellow powder, melting point: 199-201 ° C, yield: 52
% IRν _max (KBr): 3428, 2980, 169
0, 1606, 1534, 1474, 1410, 136
6,1310,1232,1194,1124,107
0,1004,934,862,822,774,76
0 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 1.23 (3
H, t, J = 6.0 Hz, 2.69 (2H, q, J =
6.0 Hz), 5.69 (2H, s), 6.70-7.
90 (10H, m).

Example 50 2-Butyl-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] thieno [3,3
4-d] imidazole-6-carboxylic acid Properties: yellow powder, melting point: 157-159 ° C, yield: 5
0.0% IRν _max (KBr): 3432, 2960, 287
2,1960,1600,1532,1480,144
8, 1392, 1320, 1222, 1184, 112
4,936,756 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.90 (3
H, t, J = 6.0 Hz), 1.09-1.96 (4
H, m), 2.70 (2H, t, J = 6.0 Hz),
5.80 (2H, s), 7.00-7.90 (10H,
m).

Example 51 2-Cyclopropyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid Properties : Yellow powder, melting point: 169-172 [deg.] C., yield: 4
0.0% IRν _max (KBr): 3432, 2980, 289
6,1686,1596,1542,1480,144
8, 1362, 1310, 1244, 1206, 117
8, 1120, 1084, 856, 758 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.49-1.
00 (4H, m), 1.30-1.70 (1H, m),
5.69 (2H, s), 6.70-7.59 (10H,
m).

Example 52 1-[[4- (1-carboxy-1-phenyl) methoxyphenyl] methyl] -2-propylthieno [3,4-
d] Imidazole-6-carboxylic acid Properties: colorless powder, melting point: 169-171 ° C, yield: 9
6.5% IRν _max (KBr): 2968, 1701, 161
4,1587,1512,1455,1368,123
9, 1179, 1119, 1086, 1050, 102
6,951,831,783,723 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.94 (3
H, t, J = 7.0 Hz), 1.40-1.89 (2
H, m), 2.66 (2H, t, J = 7.0 Hz),
5.57 (1H, s), 5.75 (2H, s), 6.7
5-7.10 (4H, m), 7.20-7.65 (5
H, m).

Example 53 2-Propyl-1-[[5'-chloro-2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-6-carboxylic acid Properties: pale yellow powder, melting point: 178-180 ° C, yield: 7
4.1% IRν _max (KBr): 1692, 1599, 152
1,1464, 1398, 1359, 1326, 128
4,1248,1194,1119,1089,101
1,936,879,855,822,780 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.97 (3
H, t, J = 7.1 Hz), 1.50-2.00 (2
H, m), 2.64 (2H, t, J = 7.5 Hz),
5.78 (2H, s), 6.90-7.10 (4H,
m), 7.25-7.55 (2H, m), 7.76 (1
H, d, J = 8.8 Hz).

Example 54 2-Propyl-4-methyl-1H-thieno [3,4-
d] Methyl imidazole-6-carboxylate 230 mg methyl 3-butyrylamino-5-methyl-4-nitrothiophene-2-carboxylate and methanol 15
ml and THF (5 ml) were added and dissolved. Under ice cooling, concentrated hydrochloric acid (9.2 ml) was added and the mixture was heated to 50 ° C. and about 10 mg of 301 mg of tin was added and stirred for 10 minutes. Stir for 2 hours at the same temperature. The reaction mixture was poured into ice water, saturated saturated aqueous sodium hydrogen carbonate was added, and the pH was adjusted to 7
Adjust to ~ 8 and extract with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The ethyl acetate layer was distilled off under reduced pressure, the obtained oily substance was dissolved in 6 ml of methanol, 504 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 50 ° C. for 4 hours and then heated under reflux for 1 hour. Saturated saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice cooling to adjust the pH to 7 to 8, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure and the resulting oil was subjected to silica gel column chromatography to give 2-propyl-4-methyl-1H-thieno [3 as a pale yellow candy from the eluate of chloroform-methanol (200: 1). , Methyl 4-d] imidazol-6-carboxylate (108 mg, yield 56.5%) is obtained. IRν _max (KBr): 2960, 2928, 169
4, 1626, 1556, 1438, 1384, 137
2,1312,1216,1110,1086,910
cm ^-1 . NMR (CDCl ₃ ) δ: 1.00 (3H, t, J =
6.5 Hz), 1.53-2.00 (2H, m), 2.
62 (3H, s), 2.75 (2H, t, J = 6.5H
z), 3.83 (3H, s).

The following compound is obtained in the same manner as in Example 1. Example 55 6-Methyl-2-propyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl]
Methyl] thieno [3,4-d] imidazole-4-carboxylate Methyl properties: pale yellow candy, yield: 31.3% IRν _max (neat): 2950,1692,148
2,1448,1436,1406,1392,132
8, 1290, 1194, 1108, 908 cm ^-1 . NMR (CDCl ₃ ) δ: 0.92 (3H, t, J =
7.5 Hz), 1.54-1.96 (2H, m), 2.
11 (3H, s), 2.68 (2H, t, J = 7.5H
z), 3.92 (3H, s), 5.12 (2H, s),
6.67-8.02 (23H, m).

The following compound is obtained as in Example 26. Example 56 6-Methyl-2-propyl-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4-carboxylic acid Properties : Pale yellow powder, melting point: 166-172 [deg.] C., yield: 6
4.0% IRν _max (KBr): 3032, 2964, 292
8,2856,1686,1538,1480,145
0,1408,1262,1198,1176,112
0,1090,1076,758 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 1.00 (3
H, t, J = 7.5 Hz), 1.54-1.96 (2
H, m), 2.32 (3H, s), 2.79 (2H,
t, J = 7.5 Hz), 5.30 (2H, s), 6.8
3-7.73 (8H, m).

Example 57 Methyl 2-propyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate 2-Propyl-1-[[2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methyl] thieno [3,4-d] imidazole-6-carboxylate (321.2 mg) is dissolved in DMF (10 ml), triethylamine (0.15 ml) and trityl chloride (293.5 mg) are added under ice cooling, and the mixture is stirred at room temperature for 45 minutes. Saturated ammonium chloride aqueous solution was added to the reaction mixture,
Extract with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to give 2-propyl-1- [as a pale yellow powder having a melting point of 183-184 ° C. from an elution part of ethyl acetate-hexane (1: 2). Methyl [2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (312.4 mg, yield 63.6%) was added. obtain. IRν _max (KBr): 1713, 1593, 154
2,1491,1467,1452,1401,137
7,1329,1233,1182,1155,110
7,1047,1026,909,762,747,6
99,678 cm ^-1 . NMR (CDCl ₃ ) δ: 0.90 (3H, t, J =
7.3 Hz), 1.50-1.90 (2H, m), 2.
52 (2H, t, J = 7.5 Hz), 3.68 (3H,
s), 5.73 (2H, s), 6.70-7.54 (2
3H, m), 7.70-7.98 (1H, m).

Example 58 6-Hydroxymethyl-2-propyl-1-[[2'-
(1-Trityltetrazol-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazole Under an argon atmosphere, 2-propyl-1-[[2 '-(1
-Trityltetrazol-5-yl) biphenyl-4-
Il] methyl] thieno [3,4-d] imidazole-6
-Dissolve 70 mg of methyl carboxylate in 6 ml of THF,
Excess lithium aluminum hydride is added under ice cooling, and the mixture is stirred at room temperature for 5 minutes. Sodium sulfate / 1 in the reaction mixture
Add 0 hydrate, dilute with ether and filter. The residue obtained after evaporation of the solvent under reduced pressure was subjected to silica gel column chromatography, and 6-hydroxymethyl-2-propyl-1- was obtained from the elution part of ethyl acetate-hexane (2: 1).
[[2 '-(1-Trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole (50.7 mg, yield 75.7%) is obtained. IRv _max (neat): 2962, 1635, 148
5,1449,1410,1392,1359,133
8, 1320, 1197, 1065, 1029, 100
2,909,879,729,699,639 cm ^-1 . NMR (CDCl ₃ ) δ: 0.95 (3H, t, J =
7.1 Hz), 1.60-2.20 (2H, m), 2.
59 (2H, t, J = 7.5Hz), 4.35 (2H,
s), 5.20 (2H, s), 6.70-7.63 (2
3H, m), 7.73-8.00 (1H, m).

Example 59 6-Hydroxymethyl-2-propyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole 6-hydroxymethyl-2-propyl-1-[[2'-
(1-Trityltetrazol-5-yl) biphenyl-
50.7 mg of 4-yl] methyl] thieno [3,4-d] imidazole is dissolved in 6 ml of THF, 3 ml of 2N-hydrochloric acid is added under ice cooling, and the mixture is stirred overnight at room temperature. Under ice-cooling, 10% sodium hydroxide was added to the reaction mixture to adjust the pH to 11, and the mixture was washed with ether. Add 2N-hydrochloric acid to the aqueous layer and p
After adjusting to H5, it was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated brine and dried over anhydrous magnesium sulfate. When ethyl acetate was distilled off under reduced pressure, the melting point was 121-125.
6-Hydroxymethyl-2-propyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d as a pale yellow powder at 0 ° C (decomposition). ] Imidazole (31.8 mg, yield 9
7.7%). IRν _max (KBr): 2968, 2926, 286
6,1533,1485,1455,1410,135
9,1065,1005,756,693 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD) δ: 0.96 (3
H, t, J = 7.1 Hz), 1.50-2.00 (2
H, m), 2.65 (2H, t, J = 7.5 Hz),
4.46 (2H, s), 5.28 (2H, s), 6.7
0 (1H, s), 6.83-7.13 (4H, m),
7.30-7.60 (3H, m), 7.67-7.90
(1H, m).

Example 60 Methyl 3-butyrylamino-5-bromomethyl-4-nitrothiophene-2-carboxylate 10 ml of carbon tetrachloride containing 143 mg of methyl 3-butyrylamino-5-methyl-4-nitrothiophene-2-carboxylate 98 mg of N-bromosuccinimide and 8.6 mg of benzoyl peroxide are added to the solution, and the mixture is heated under reflux for 1 hour and 30 minutes. The solvent of the reaction mixture is evaporated under reduced pressure and extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
Methyl 3-butyrylamino-5-bromomethyl-4-nitrothiophene-2-carboxylate (122 mg, yield 66.8%) was obtained as a pale yellow powder from the eluate of 4). IRν _max (KBr): 3292, 2964, 170
4,1682,1568,1530,1500,144
0,1414,1362,1290,1218,120
4,1136,1116,1102,920,694
616 cm ^-1 . NMR (CDC1 ₃ ) δ: 1.01 (3H, t, J =
7.0 Hz), 1.50-2.00 (2H, m), 2.
42 (2H, t, J = 7.0Hz), 3.92 (3H,
s), 4.82 (2H, s), 9.24 (1H, b
s).

Example 61 Methyl 3-butyrylamino-5-morpholinomethyl-4-nitrothiophene-2-carboxylate 10 ml THF containing 547.5 mg methyl 3-butyrylamino-5-bromomethyl-4-nitrothiophene-2-carboxylate. Morpholine 0.26 ml under ice cooling
Is added dropwise, and the mixture is stirred at the same temperature for 1 hour. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained oily substance was subjected to silica gel column chromatography. From the elution part of ethyl acetate-hexane (1: 3), as yellow amorphous crystals, 3-butyrylamino-5-morpholinomethyl- was obtained. Methyl 4-nitrothiophene-2-carboxylate (250.5 mg, yield 45.0%) is obtained. IRν _max (KBr): 3286, 2956, 172
8, 1683, 1575, 1527, 1503, 145
5,1434,1416,1362,1293,127
8,1263,1194,1137,1116,109
2,1065,861 cm ^-1 . NMR (CDC1 ₃ ) δ: 1.00 (3H, t, J =
7.1 Hz), 1.50-1.97 (2H, m), 2.
40 (2H, t, J = 7.3Hz), 2.52-2.7
4 (4H, m), 3.68-3.83 (4H, m),
3.91 (3H, s), 3.94 (2H, s), 9.2
4 (1H, bs).

The following compounds are obtained as in Example 61. Example 62 Methyl 3-butyrylamino-4-nitro-5- (4-phenylpiperazinylmethyl) thiophene-2-carboxylate Property: Yellowish amorphous, yield: 66.8% IRv _max (KBr): 3300, 2960, 287
2,2828,1722,1682,1600,157
4,1524,1502,1358,1270,120
6,1106 cm ^-1 . _{NMR (CDC1 3 + CD 3 OD} ) δ: 1.00 (3
H, t, J = 7.0 Hz), 1.51-1.92 (2
H, m), 2.41 (2H, t, J = 7.0 Hz),
2.61-2.93 (4H, m), 3.06-3.37
(4H, m), 3.90 (3H, s), 4.01 (2
H, s), 6.68-7.38 (5H, m), 9.23.
(1H, bs).

Example 63 4-morpholinomethyl-2-propylthieno [3,4-
d] Methyl imidazole-6-carboxylate Methyl 3-butyrylamino-5-morpholinomethyl-4-nitrothiophene-2-carboxylate 227.3 mg was dissolved in 7 ml of methanol and 3 ml of THF, and 5 ml of concentrated hydrochloric acid was added under ice cooling. Heated to ℃, 218.2mg
After about 10 mg of tin is added and stirred for 10 minutes, the reaction mixture is ice-cooled, the remaining tin is added little by little, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into ice water, saturated aqueous sodium hydrogen carbonate is added to adjust the pH to 7 to 8, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate layer was evaporated under reduced pressure, the obtained oily substance was dissolved in 7 ml of methanol, and 465.6 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 50 ° C. for 2 hours.
Stir for hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice cooling and p
Adjust to H7-8 and extract with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting oily substance was subjected to silica gel column chromatography, and 4-morpholinomethyl-2-propylthieno [3,3] was obtained as a yellow candy from the eluate of chloroform-methanol (100: 1). Methyl 4-d] imidazole-6-carboxylate (118.1 mg, yield 60.1%) is obtained. IRν _max (neat): 2962,1692,162
6,1554,1440,1383,1317,121
8,1110,912,729,645 cm ^-1 . NMR (CDC1 ₃ ) δ: 1.02 (3H, t, J =
7.3 Hz), 1.56-2.02 (2H, m), 2.
40-2.64 (4H, m), 2.78 (2H, t, J
= 7.3 Hz), 3.57-3.80 (4H, m),
3.87 (3H, s), 3.96 (2H, s).

The following compound is obtained as in Example 63. Example 64 Methyl 4- (4-phenylpiperazinylmethyl) -2-propylthieno [3,4-d] imidazol-6-carboxylate Property: Light brown oil, yield: 28.8% IRν _max ( neat): 2964, 2824, 169
2,1600, 1554, 1502, 1438, 138
4,1326,1228,1112,910,760c
m ^-1 . NMR (CDC1 ₃ ) δ: 1.10 (3H, t, J =
7.0 Hz), 1.86 (2H, quin, J = 7.0)
Hz), 2.61-2.92 (6H, m), 3.07-
3.36 (4H, m), 3.86 (3H, s), 4.1
3 (2H, s), 6.72-7.36 (5H, m).

Example 65 4-morpholinomethyl-2-propyl-1-[[2'-
(1-Trityltetrazol-5-yl) biphenyl-
Methyl 4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate and 6-morpholinomethyl-
Methyl 2-propyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4-carboxylate 60% under an argon atmosphere. Sodium hydride 9.9mg
Anhydrous DMF (1 ml) was added to the mixture, and anhydrous DMPC containing methyl 4-morpholinomethyl-2-propylthieno [3,4-d] imidazole-6-carboxylate 65.9 mg under ice cooling.
Add F2 ml solution and stir at the same temperature for 30 minutes. Under ice cooling, N-trityl-5- [4 '-(bromomethyl) was added to this.
A solution of 137.2 mg of biphenyl-2-yl] tetrazole in 2 ml of anhydrous DMF was added, and the mixture was heated at 0 ° C. for 5 hours 15
Stir for 30 minutes at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting oily substance was subjected to silica gel column chromatography, and 4-morpholinomethyl-2-propyl-as yellow candy was obtained from the elution part of ethyl acetate-hexane (2: 1).
1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-
d] Methyl imidazole-6-carboxylate (92.5 m
g, yield 56.5%) and its isomer, 6-morpholinomethyl-2-propyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno. [3,4-d] imidazol-4-
Methyl carboxylate (7.7 mg, 4.7% yield) is obtained.

4-morpholinomethyl-2-propyl-1
-[[2 '-(1-Trityltetrazol-5-yl)
Biphenyl-4-yl] methyl] thieno [3,4-d]
Methyl imidazole-6-carboxylate IRv _max (neat): 2956, 2854, 287
2,1695,1449,1329,1242,111
3,909,729,696 cm ^-1 . NMR (CDC1 ₃ ) δ: 0.89 (3H, t, J =
7.0 Hz), 1.50-1.93 (2H, m), 2.
36-2.77 (6H, m), 3.60-3.85 (4
H, m), 3.69 (3H, s), 4.02 (2H,
s), 5.71 (2H, s), 6.67-7.60 (2
1H, m), 7.73-8.04 (2H, m). 6-morpholinomethyl-2-propyl-1-[[2'-
(1-Trityltetrazol-5-yl) biphenyl-
Methyl 4-yl] methyl] thieno [3,4-d] imidazole-4-carboxylate IRv _max (neat): 2956, 2926, 285
4,1695,1449,1329,1287,90
9,729,696,642 cm ^-1 . NMR (CDC1 ₃ ) δ: 0.95 (3H, t, J =
7.3 Hz), 1.50-1.94 (2H, m), 2.
08-2.37 (4H, m), 2.72 (2H, t, J
= 7.3 Hz), 3.17 (2H, s), 3.40-
3.70 (4H, m), 3.95 (3H, s), 5.4
3 (2H, s), 6.67-7.60 (22H, m),
7.70-7.95 (1H, m).

The following compounds are obtained as in Example 65. Example 66 4- (4-phenylpiperazinylmethyl) -2-propyl-1-[[2 '-(1-trityltetrazole-5-
Il) biphenyl-4-yl] methyl] thieno [3,4
-D] Methyl imidazole-6-carboxylate Properties: Light yellow candy, yield 48.2% IRv _max (neat): 2952, 2820, 169
4,1600,1550,1494,1448,139
8, 1376, 1330, 1302, 1236, 118
6,1142,1098,1064,1006,90
8,758,730 cm ^-1 . NMR (CDC1 ₃ ) δ: 0.92 (3H, t, J =
7.0 Hz), 1.74 (2H, quin, J = 7.0)
Hz), 2.53 (2H, t, J = 7.0Hz), 2.
66-2.93 (4H, m), 3.06-3.36 (4
H, m), 3.66 (3H, s), 4.09 (2H,
s), 5.72 (2H, s), 6.70-7.94 (2
8H, m).

6- (4-phenylpiperazinylmethyl)
Methyl 2-propyl-1-[[2 '-(1-trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-4-carboxylate Properties: Light yellow candy , Yield: 15.8% IRv _max (neat): 2952, 2820, 169
6,1600, 1482, 1450, 1408, 138
8, 1328, 1290, 1232, 1194, 110
8,1006,910,730 cm ^-1 . NMR (CDC1 ₃ ) δ: 0.95 (3H, t, J =
7.0 Hz), 1.86 (2H, quin, J = 7.0)
Hz), 2.16-2.53 (4H, m), 2.84
(2H, t, J = 7.0Hz), 2.87-3.34.
(4H, m), 3.23 (2H, s), 3.95 (3
H, s), 5.45 (2H, s), 6.68-7.94.
(28H, m).

The following compound is obtained as in Example 26. Example 67 4-morpholinomethyl-2-propyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazol-6-
Carboxylic acid Properties: Yellowish powder, melting point: 158-163 ° C (decomposition),
Yield: 59.6% IRν _max (KBr): 3406, 2962, 286
6,1680,1602,1545,1500,145
2,1404,1356,1239,1200,117
6,1110,1053,957,936,756cm
^-1 . NMR (CDC1 ₃ + CD ₃ OD + D ₂ O) δ: 0.9
3 (3H, t, J = 7.3Hz), 1.43-1.84
(2H, m), 2.43-2.93 (6H, m), 3.
50-3.83 (2H, m), 4.14 (2H, s),
5.74 (2H, s), 6.86-7.13 (4H,
m), 7.20-7.60 (3H, m), 7.70-
7.87 (1H, m).

The following compound is obtained as in Example 26. Example 68 4- (4-phenylpiperazinylmethyl) -2-propyl-1-[[2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl] thieno [3,4-d]
Imidazole-6-carboxylic acid Properties: yellowish powder, melting point: 162-169 ° C (decomposition),
Yield: 50.2% IRν _max (KBr): 2950, 1680, 160
0,1546,1498,1452,1402,135
6,1232,1206,1178,934,758c
m ^-1 . _{NMR (CDC1 3 + DMSO-d} 6) δ: 0.96
(3H, t, J = 7.0Hz), 1.52-1.98
(2H, m), 2.62 (2H, t, J = 7.0H
z), 2.70-2.96 (4H, m), 3.02-
3.45 (4H, m), 4.06 (2H, s), 5.8
0 (2H, s), 6.71-7.83 (13H, m).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/415 AEQ 9360-4C (72) Inventor Takehiro Uchibori 2-6 Sakura-cho, Segami-cho, Fukushima-shi, Fukushima Prefecture -5 (72) Inventor Kentaro Furushiro 9-6 Guroji, Koriyama, Shiroishi, Miyagi Prefecture (72) Inventor Senichi Narita 1-8-2-902, Iriya, Taito-ku, Tokyo

Claims (7)

[Claims] 1. A general formula: [Wherein R ¹ and R ² are a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group, a hydroxyalkyl group, a lower alkoxy group, a formyl group, a cyano group, a carbamoyl group, a lower alkoxycarbonyl group, a carboxy group, and (In the formula, R ⁶ may be a hydrogen atom, an alkyl group, R ⁷ and R ⁸ may be the same or different, and a hydrogen atom, a lower alkoxycarbonyl group, a carboxy group, an optionally protected tetrazole group or an aralkyl group, R ⁹ , R ¹⁰ may be the same or different, hydrogen atom, alkyl group, optionally substituted aryl group or aralkyl group, V is oxygen atom, nitrogen atom, carbon atom, sulfur atom, ═CH—R ¹¹ or = N-R ^11, R ¹¹ is alkyl, substituted optionally may be an aryl group, an aralkyl group or an aroyl group, m is an integer from 1 to 6, q is an integer of 1 to 3), an aryl group or an aralkyl group, R ³ is an alkyl group, a cyclo-lower alkyl group or a lower alkylthio group, R ⁴ is a hydrogen atom, a nitro group, a cyano group, an optionally substituted amino group, a lower alkoxy Carbonyl group, a carboxy group or a protected or unprotected tetrazole group, R ⁵ is a hydrogen atom, a halogen atom or a lower alkoxy group, A is ## STR3 ## (In the formula, X represents a single bond or a bond through a spacer having two or less atomic chains, Y represents a methylene carbon,
A group represented by an optionally substituted nitrogen atom, oxygen atom or sulfur atom]] or a salt thereof. 2. A general formula: [In the formula, R ¹ and R ² hydrogen atoms, hydroxyl groups, halogen atoms,
Alkyl group, hydroxyalkyl group, lower alkoxy group, formyl group, cyano group, carbamoyl group, lower alkoxycarbonyl group, carboxy group, (In the formula, R ⁶ is a hydrogen atom, an alkyl group, R ⁷ and R ⁸ are the same or different hydrogen atoms, a lower alkoxycarbonyl group, a carboxy group, an optionally protected tetrazole group or an aralkyl group, R ⁹ , R ¹⁰ may be the same or different, a hydrogen atom, an alkyl group, an optionally substituted aryl group or aralkyl group, V is an oxygen atom,
Nitrogen atom, carbon atom, sulfur atom, ═CH—R ¹¹ or ═N—R ¹¹ , R ¹¹ alkyl group, optionally substituted aryl group, aralkyl group or aroyl group, m is an integer of 1 to 6, q Represents an integer of 1 to 3), an aryl group or an aralkyl group, and R ³ represents an alkyl group, a cyclo-lower alkyl group or a lower alkylthio group], or a salt thereof. [Wherein R ⁴ is a hydrogen atom, a nitro group, a cyano group, an optionally substituted amino group, a lower alkoxycarbonyl group, a carboxy group or an optionally protected tetrazole group, and R ⁵ is a hydrogen atom or a halogen atom. Or a lower alkoxy group, A is (In the formula, X represents a single bond or a bond through a spacer having two or less atomic chains, Y represents a methylene carbon,
A nitrogen atom, an oxygen atom or a sulfur atom which may be substituted), W represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group]. Item 1. A method for producing a thieno [3,4-d] imidazole derivative (I) or a salt thereof according to item 1. 3. A general formula: [Wherein R ¹ and R ² are hydrogen atom, hydroxyl group, halogen atom, alkyl group, hydroxyalkyl group, lower alkoxy group, formyl group, cyano group, carbamoyl group, lower alkoxycarbonyl group, carboxy group, and (In the formula, R ⁶ may be a hydrogen atom, an alkyl group, R ⁷ and R ⁸ may be the same or different, and a hydrogen atom, a lower alkoxycarbonyl group, a carboxy group, an optionally protected tetrazole group or an aralkyl group, R ⁹ , R ¹⁰ may be the same or different, hydrogen atom, lower alkyl group, optionally substituted aryl group or aralkyl group, V is oxygen atom, nitrogen atom, carbon atom, sulfur atom, ═CH—R
¹¹ or = N-R ¹¹ , R ¹¹ is an alkyl group, an optionally substituted aryl group, an aralkyl group or an aroyl group,
m is an integer of 1 to 6, q is an integer of 1 to 3), an aryl group or an aralkyl group, R ³ is an alkyl group, a cyclo-lower alkyl group or a lower alkylthio group, and R ⁵ is a hydrogen atom, a halogen atom or a lower atom. Alkoxy group, A is (In the formula, X represents a single bond or a bond through a spacer having two or less atomic chains, Y represents a methylene carbon,
A group represented by (which represents a nitrogen atom, an oxygen atom or a sulfur atom which may be substituted)] or a salt thereof is subjected to a reaction for forming a tetrazole group. Chemical 11] A method for producing a thieno [3,4-d] imidazole derivative [Ib] or a salt thereof represented by (each symbol in the formula has the above meaning). 4. A general formula: [In the formula, R ³ is an alkyl group, a cyclo lower alkyl group or a lower alkylthio group, R ⁴ is a hydrogen atom, a nitro group, a cyano group, an optionally substituted amino group, a lower alkoxycarbonyl group, a carboxy group or a protected group. Optionally a tetrazole group, R ⁵ is a hydrogen atom, a halogen atom or a lower alkoxy group, and A is (In the formula, X represents a single bond or a bond through a spacer having two or less atomic chains, Y represents a methylene carbon,
A group represented by optionally substituted nitrogen atom, oxygen atom or sulfur atom) or a salt thereof, and a compound represented by the formula R ²¹ -B, wherein R ²¹ is an alkyl group, A hydroxyalkyl group, a formyl group or a carboxy group, B represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group] under a basic condition. 14] A process for producing a thieno [3,4-d] imidazole derivative (Id) represented by [each symbol in the formula has the above meaning] or a salt thereof. 5. A general formula: [Wherein R ¹ and R ² are hydrogen atom, hydroxyl group, halogen atom, alkyl group, hydroxyalkyl group, lower alkoxy group, formyl group, cyano group, carbamoyl group, lower alkoxycarbonyl group, carboxy group, and (In the formula, R ⁶ may be a hydrogen atom, an alkyl group, R ⁷ and R ⁸ may be the same or different, and a hydrogen atom, a lower alkoxycarbonyl group, a carboxy group, an optionally protected tetrazole group or an aralkyl group, R ⁹ , R ¹⁰ may be the same or different, hydrogen atom, lower alkyl group, optionally substituted aryl group or aralkyl group, V is oxygen atom, nitrogen atom, carbon atom, sulfur atom, ═CH—R
¹¹ or = N-R ¹¹ , R ¹¹ is an alkyl group, an optionally substituted aryl group, an aralkyl group or an aroyl group,
m is an integer of 1 to 6, q is an integer of 1 to 3), an aryl group or an aralkyl group, R ³ is an alkyl group, a cyclo-lower alkyl group or a lower alkylthio group, and R ⁴ is a hydrogen atom, a nitro group, or cyano. A group, an optionally substituted amino group, a lower alkoxycarbonyl group, a carboxy group or an optionally protected tetrazole group, R ⁵ is a hydrogen atom, a halogen atom or a lower alkoxy group, and A is (In the formula, X represents a single bond or a bond through a spacer having two or less atomic chains, Y represents a methylene carbon,
(Representing a group represented by optionally substituted nitrogen atom, oxygen atom or sulfur atom) or a salt thereof, and further performing an intramolecular ring-closing reaction, A method for producing the thieno [3,4-d] imidazole derivative according to claim 1 or a salt thereof. 6. A general formula: [Wherein R ¹ and R ² are hydrogen atom, hydroxyl group, halogen atom, alkyl group, hydroxyalkyl group, lower alkoxy group, formyl group, cyano group, carbamoyl group, lower alkoxycarbonyl group, carboxy group, and (In the formula, R ⁶ may be a hydrogen atom, an alkyl group, R ⁷ and R ⁸ may be the same or different, and a hydrogen atom, a lower alkoxycarbonyl group, a carboxy group, an optionally protected tetrazole group or an aralkyl group, R ⁹ , R ¹⁰ may be the same or different, hydrogen atom, alkyl group, optionally substituted aryl group or aralkyl group, V is oxygen atom, nitrogen atom, carbon atom, sulfur atom, ═CH—R ¹¹ or = N-R ^11, R ¹¹ is alkyl, substituted optionally may be an aryl group, an aralkyl group or an aroyl group, m is an integer from 1 to 6, q is an integer of 1 to 3), an aryl group or an aralkyl Group, R ⁴ is a hydrogen atom, a nitro group,
A cyano group, an optionally substituted amino group, a lower alkoxycarbonyl group, a carboxy group or an optionally protected tetrazole group, R ⁵ is a hydrogen atom, a halogen atom or a lower alkoxy group, and A is (In the formula, X represents a single bond or a bond through a spacer having two or less atomic chains, Y represents a methylene carbon,
An optionally substituted nitrogen atom, the compound represented by the oxygen atom or an sulfur atom) a group represented by] or a salt thereof, the general formula R ³ -U (VI) (wherein, R ³ Is an alkyl group, a cyclo lower alkyl group or a lower alkylthio group, U is an imino lower alkyl ether, an imino lower alkyl thioether, a carboxy group,
A compound represented by (which represents an amidine group, an aldehyde group or a cyano group) is reacted.
Thieno [3,4-d] imidazole derivative described in [1]
Or the manufacturing method of the salt. 7. A circulatory organ agent containing the thieno [3,4-d] imidazole derivative [1] or the salt thereof according to claim 1 as an active ingredient.